Injectable capsaicin

ABSTRACT

The present invention provides compositions and methods for relieving pain at a site in a human or animal in need thereof by administering at a discrete site in a human or animal in need thereof a dose of capsaicin in an amount effective to denervate a discrete site without eliciting an effect outside the discrete location, the dose of capsaicin ranging from 1 μg to 3000 μg.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/434,453, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,530, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,500, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,828, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,452, filed Dec. 18,.2002, U.S. Provisional PatentApplication No. 60/434,501, filed Dec. 18, 2002, and U.S. ProvisionalPatent Application No. 60/461,164, filed Apr. 8, 2003, the disclosuresof which is hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This application is directed to compositions and methods for relievingpain at a specific site, for example, associated with inflammation ofjoints, tendons, nerves, muscle, and other soft tissues, nerve injuryand neuropathies, and pain from tumors in soft tissues or bone.

BACKGROUND OF THE INVENTION

Capsaicin, a pungent substance derived from the plants of the solanaceaefamily (hot chili peppers) has long been used as an experimental toolbecause of its selective action on the small diameter afferent nervefibers C-fibers and A-delta fibers that are believed to signal pain.From studies in animals, capsaicin appears to trigger C-fiber membranedepolarization by opening cation channels permeable to calcium andsodium. Recently one of the receptors for capsaicin effects has beencloned. Capsaicin can be readily obtained by ethanol extraction of thefruit of capsicum frutescens or capsicum annum. Capsaicin is known bythe chemical nameN-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide. Capsaicin ispractically insoluble in water, but freely soluble in alcohol, ether,benzene and chloroform. Therapeutically capsaicin has been used as atopical analgesic. Capsaicin is available commercially as Capsaicin USPfrom Steve Weiss & Co., 315 East 68^(th) Street, New York, N.Y. 10021and can also be prepared synthetically by published methods. SeeMichalska et al., “Synthesis and Local Anesthetic Properties ofN-substituted 3,4-Dimethoxyphenethylamine Derivatives”, Diss Pharm.Pharmacol., Vol. 24, (1972), pp. 17-25, (Chem. Abs. 77: 19271a),discloses N-pentyl and N-hexyl 3,4-dimethoxyphenylacetamides which arereduced to the respective secondary amines.

Capsaicin is listed in the pharmacopoeias of the United Kingdom,Australia, Belgium, Egypt, Germany, Hungary, Italy, Japan, Poland,Portugal, Spain, and Switzerland and has previously been listed in theUnited States Pharmacopoeia and the National Formulary. The FDA proposedmonographs on analgesic drug products for over-the-counter (OTC) humanuse. These include capsaicin and capsicum preparations that are regardedas safe and effective for use as OTC external analgesics. Capsaicin isthe only chemical entity of Capsicum recognized by the FDA. Capsaicin(USP) contains not less than 110% total capsaicinoids which typicallycorresponds to 63% pure capsaicin. USP capsaicin is trans-capsaicin(55-60%) and also contains the precursors dihydrocapsaicin andnordihydrocapsaicin.

Capsaicin mediated effects include: (i) activation of nociceptors inperipheral tissues; (ii) eventual desensitization of peripheralnociceptors to one or more stimulus modalities; (iii) cellulardegeneration of sensitive A-delta and C-fiber afferents; (iv) activationof neuronal proteases; (v) blockage of axonal transport; and (vi) thedecrease of the absolute number of nociceptive fibers without affectingthe number of non-nociceptive fibers.

The dosage forms of capsaicin which have been most widely studiedclinically are capsaicin containing creams (Zostrix, Zostrix-HP, andAxsain). These products have been examined in a broad spectrum ofpainful conditions including osteoarthritis. However the efficacy oftopically administered capsaicin in arthritis in general has proven tobe limited.

Prior publications describe topical administration of capsaicin for thetreatment of various conditions. For example, U.S. Pat. No. 4,997,853(Bernstein) describes methods and compositions utilizing capsaicin as anexternal analgesic. U.S. Pat. No. 5,063,060 (Bernstein) describescompositions and methods for treating painful, inflammatory or allergicdisorders. U.S. Pat. No. 5,178,879 (Adekunle, et al.) describes methodsfor preparing a non-greasy capsaicin gel for topical administration forthe treatment of pain. U.S. Pat. No. 5,296,225 (Adekunle, et al)describes indirect methods of treating orofacial pain with topicalcapsaicin. U.S. Pat. No. 5,665,378 (Davis, et al.) describes transdermaltherapeutic formulations comprising capsaicin, a nonsteroidalanti-inflammatory agent and pamabrom for the treatment of pain. U.S.Pat. No. 6,248,788 (Robbins, et al.) describes administration of 7.5%capsaicin cream in combination with marcaine epidural injections inpatients suffering from long-term persistent foot pain. U.S. Pat. No.6,239,180 (Robbins) describes combining capsaicin loaded patches withlocal anesthesia to treat peripheral neuropathy. The use of topicalcapsaicin has also been described in the art to treat conditions asdiverse as post mastectomy pain syndrome (Watson and Evans, Pain 51:375-79 (1992)); painful diabetic neuropathy (Tandan et al., DiabetesCare 15: 8-13 (1992)); The Capsaicin Study Group, Arch Intern Med 151:2225-9(1991); post-herpetic neuralgia (Watson et al., Pain 33: 333-40(1988)), Watson et al., Clin. Ther. 15: 510-26 (1993); Bernstein et al.,J. Am Acad Dermatol 21: 265-70 (1989) and pain in Guillian-Barresyndrome (Morganlander et al., Annals of Neurology 29:199 (1990)).Capsaicin has also been used in the treatment of osteoarthritis (Deal etal., Clin Ther 13: 383-95 (1991); McCarthy and McCarthy, J. Rheumatol19: 604-7 (1992); Altman et al., Seminars in Arthritis and Rheumatism23: 25-33 (1994). In addition, U.S. Pat. No. 4,599,342 (LaHann)describes oral and subcutaneous or intramuscular administration of acombination of capsaicin or a capsaicin analog with an opioid analgesic.U.S. Pat. No. 4,313,958 (LaHann) describes intrathecal, epidural,intramuscular, intravenous, intraperitoneal and subcutaneousadministration of capsaicin utilizing a “stair-step” dosing pattern.

Humans have long been exposed to dietary sources of capsaicin-containingspices and to topical preparations used for a variety of medicalindications. This vast experience has not revealed significant orlasting adverse effects of capsaicin exposure. The recent determinationof capsaicin's potential therapeutic effects on unmyelinated sensoryafferent nerve fibers require diligent consideration of this compoundfor further pharmaceutical development.

Because of the ability of capsaicin to desensitize nociceptors inperipheral tissues, its potential analgesic effects have also beenassessed in various clinical trials. However, since the application ofcapsaicin itself frequently causes burning pain and hyperalgesia apartfrom the neuropathic pain being treated, patient compliance has beenpoor and the drop out rates during clinical trials have exceeded fiftypercent. The spontaneous burning pain and hyperalgesia are believed tobe due to intense activation and temporary sensitization of theperipheral nociceptors at the site of capsaicin application. Thisactivation and sensitization occur prior to the desensitization phase.The activation phase could be a barrier to use of capsaicin because ofthe pain produced.

It would therefore be advantageous to provide methods and compositionsincluding capsaicin or capsaicin analogues thereof with effectiveconcentrations to cause an analgesic effect without the side effectsnormally associated with the use of capsaicin.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide compositions andmethods for providing pain relief in humans and animals by administeringan injectable or implantable dose of capsaicin or capsaicin analogue toa site for the treatment of acute or chronic pain, nociceptive andneuropathic pain, pre- and post-operative pain, cancer pain, painassociated with neurotransmitter dysregulation syndromes and orthopedicdisorders.

It is another object of the invention to provide compositions andmethods for attenuating pain at a discrete site in a human or animal viathe administration of a capsaicinoid via injection or implantation atthe discrete site.

It is another object of the present invention to provide compositionsand methods for relieving pain at an intra-articular site or at a bodyspace by administering an injectable or implantable single dose ofcapsaicin or capsaicin analogue to the intra-articular site or bodyspace.

It is a further object of the invention to provide compositions andmethods for treatment of sports-related injuries utilizing injectable orimplantable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treatment of orthopaedic disorders or injuries utilizinginjectable or implantable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating acute traumatic pain utilizing injectable orimplantable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating neuropathic pain utilizing injectable orimplantable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating nociceptive pain utilizing injectable orimplantable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating neurotransmitter-dysregulation syndromes utilizinginjectable or implantable capsaicinoids.

In accordance with the above objects and others, in certain embodimentsof the present invention, there is provided a method for attenuating orrelieving pain at a site in a human or animal in need thereof,comprising administering via injection or implantation at a discretesite in a human or animal in need thereof a dose of capsaicin in anamount effective to denervate the discrete site without eliciting aneffect outside the discrete location and to attenuate pain emanatingfrom said site, the dose ranging from about 1 μg to about 5,000 μgcapsaicin or a therapeutically equivalent dose of a capsaicinoid otherthan capsaicin. In other words, the term “capsaicinoid” is meant toencompass formulations where the drug is capsaicin, a capsaicinoid otherthan capsaicin, or a mixture of capsaicin with one or more othercapsaicinoids (the total amount of all capsaicinoid drug being based ona therapeutically equivalent dose to dose from about 1 μg to about 5,000μg capsaicin).

In certain preferred embodiments of the present invention, the dose ofcapsaicinoid contained in a unit dose injection/implantation is fromabout 1 μg to about 5000 μg of capsaicin, preferably from about 10 μg toabout 3000 μg capsaicin, more preferably from about 300 μg to about 1500μg capsaicin, or a therapeutically equivalent amount of one or morecapsaicinoids. In certain preferred embodiments, the dose of capsaicinis from about 400 μg to about 1200 μg, or a therapeutically equivalentamount of one or more capsaicinoids. In certain other embodiments, thedose of capsaicin is preferably from about 10 μg to about 1000 μg, morepreferably from about 20 μg to about 300 μg, and most preferably fromabout 35 μg to about 200 μg. Preferably, the capsaicinoid isadministered in a pharmaceutically and physiologically acceptablevehicle for injection or implantation, which may optionally furtherinclude one or more additional pharmaceutical excipients.

The dose of capsacinoid may be injected or implanted subcutaneously,intramuscularly, itrathecally, epidurally, intraperitoneally, caudallyintradermally or intracutaneously, intercostally at a single nerve,intra-articularly, intrasynovially, intraspinally, intra-arterially orinto body spaces. Intra-articular administration of the formulations ofthe invention may be, e.g., into a joint selected from the groupconsisting of knee, elbow, hip, sternoclavicular, temporomandibular,carpal, tarsal, wrist, ankle, intervertebral disk, ligamentum flavum andany other joint subject to pain.

In certain preferred embodiments, a local anesthetic may be administeredprior to or concurrently with said dose of capsaicinoid in an amount andlocation effective to attenuate an initial hyperalgesic effect of theadministered dose of capsaicinoid. The local anesthetic may beadministered, e.g., by direct injection into the site where said dose ofcapsaicinoid is administered, or as a proximal, regional, somatic, orneuraxial block. General anesthesia may be used, if necessary.

In certain embodiments, the administration of capsaicinoid at thediscrete site provides pain attenuation or pain relief for at leastabout 48 hours to about 16 weeks.

The invention is further directed in part to a method of treating acutetraumatic pain associated with an injury, comprising injecting acapsaicinoid in a physiologically compatible vehicle through the skin ofa patient in proximity to an injury, said dose of capsaicinoid beingsufficient to attenuate the dull, aching pain associated with C-fibersin proximity to the injury and such that the patient continues to havesensation in proximity to the injury and without affecting sharpprotective pain associated with A-delta fibers in proximity to the site,the dose of capsaicinoid being therapeutically equivalent to a dose ofcapsaicin in an amount from about 300 to about 1500 μg and beingeffective to attenuate dull, aching pain in proximity to the injury forat least about 48 hours.

In certain preferred embodiments, the capsaicinoid is capsaicin itself.In more preferred embodiments, the capsaicinoid comprisestrans-capsaicin. In most preferred embodiments, the capsaicinoid is atleast about 97% trans-capsaicin.

The single injectable or implantable dose of a capsaicinoid administeredat a discrete painful site in accordance with the present invention ispreferably in an amount effective to a) produce a selective,highly-localized destruction or incapacitation of C-fibers and/orA-delta fibers in a discrete, localized area responsible for theinitiation of pain for the purpose of reducing or eliminating painarising from a discrete locus, and b) minimize potential adverseconsequences of C-fiber and/or A-delta activation and or damage outsideof the locus of pain.

The present invention is also directed to an injectable or implantablepharmaceutical composition for attenuating pain at a site in a human oranimal in need thereof, consisting essentially of from 1 μg to 5000 μgof a capsaicinoid comprising trans-capsaicin and a pharmaceuticallyacceptable vehicle for injection or implantation. In certain preferredembodiments, the dose of trans-capsaicin ranges from about 10 μg toabout 3000 μg, from about 300 μg to about 1500 μg, or preferably fromabout 400 μg to about 1200 μg.

In order that the invention described herein may be more fullyunderstood, the following definitions are provided for the purposes ofthis disclosure:

The term “injection” shall mean administration of capsaicin to adiscrete site through the skin of a human or animal.

The term “implantation” shall mean administration of capsaicin to adiscrete site by embedding the dose of capsaicin into the skin, tissue,muscles, tendons, joints, or other body parts of a human or animal.

The term “infiltration” shall mean administration into a discretesurgical site where the surgical wound is open.

As used herein, the term “capsaicinoid” means capsaicin, capsaicin USPand purified capsaicin, capsaicin analogues and derivatives thereof(collectively referred to as capsaicinoids in this specification andappended claims) that act at the same pharmacologic sites, e.g., VR1, ascapsaicin, unless otherwise specified.

Acute pain shall mean any pain that presents with a rapid onset followedby a short, severe course, e.g., headache, pain associated with cancer,fractures, strains, sprains, and dislocations of bones, joints,ligaments and tendons.

Chronic pain shall mean pain that lasts for a long period of time or ismarked by frequent recurrence, e.g., pain associated with terminalillnesses, arthritis, autoimmune diseases; or neuropathic pain caused bydegenerative diseases such as diabetes mellitus or spinal degeneration,or resulting from neural remodeling following traumatic injury orsurgery.

As used herein, the term “local anesthetic” means any drug or mixture ofdrugs that provides local numbness and/or analgesia.

By co-administration it is meant either the administration of a singlecomposition containing both the capsaicin and an additionaltherapeutically effective agent(s), e.g., local anesthetic or phenol, orthe administration of a capsaicin and the additional therapeuticallyeffective agent(s) as separate compositions within short enough timeperiods that the effective result is equivalent to that obtained whenboth compounds are administered as a single composition.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the-scope of the invention as encompassed bythe claims.

FIG. 1 is a graph displaying the plasma concentration of the 10 μg, 100μg and 300 μg doses of capsaicin administered to study subjects enteredinto the Osteoarthritis Safety Study exemplified in Example 1.

FIG. 2 is a graph displaying the percent reduction in VAS score comparedto baseline in study subjects entered into the Osteoarthritis SafetyStudy exemplified in Example 1.

FIG. 3 is a graph displaying the NRS Pain Score in study subjectsentered into the Osteoarthritis Efficacy Study exemplified in Example 2.

FIG. 4 is a graph displaying a comparison of VAS Pain Score betweensubjects entered into the Bunionectomy Efficacy study exemplified inExample 3.

FIG. 5 is a graph displaying a comparison of the percent of subjectsentered in to the Bunionectomy Efficacy study exemplified in Example 3requiring rescue medication.

DETAILED DESCRIPTION OF THE INVENTION

The compositions and methods disclosed herein can be used for treatingpain at a specific site with an effective amount of capsaicin orcapsaicin analogue, hereinafter collectively referred to as“capsaicinoids”. In one preferred embodiment, the methods involveadministration of an effective amount of capsaicinoid to a discrete sitein a human or animal for relieving pain at the site.

In another embodiment, the methods involve providing anesthesia to thesite where the capsaicinoid is to be administered, and thenadministering an effective amount of capsaicinoid to the site toattenuate the pain emanating from the site, e.g., for at least about 72hours. The anesthesia can be provided directly to the site, or at aremote site that causes anesthesia at the site where the capsaicinoid isto be administered. For example, epidural regional anesthesia can beprovided to patients to which the capsaicinoid is to be administered ata site located from the waist down. Alternatively, a local anestheticmay be administered as a regional block, a proximal block, a somaticblock, or a neuraxial block. The anesthetic may be administered as ageneral anesthetic, as a spinal block, as an epidural block, or as anerve block. Preferably, in the embodiments in which a local anestheticis administered, the local anesthetic is administered prior toadministration of the capsaicinoid, such that the local anesthetic hasprovided temporary anesthesia to the area to be treated with thecapsaicinoid.

Examples of local anesthetic agents which can be used includebupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine,prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, andxylocaine, and mixtures thereof and any other art-known pharmaceuticallyacceptable local anesthetic. The local anesthetic can be in the form ofa salt, for example, the hydrochloride, bromide, acetate, citrate,carbonate or sulfate. In certain embodiments, the local anesthetic agentis in the form of a free base. Preferred local anesthetic agentsinclude, e.g., bupivacaine or lidocaine. For bupivacaine, the free baseprovides a slower initial release and avoids an early “dumping” of thelocal anesthetic at the injection site. Other local anesthetics may actdifferently. Local anesthetic agents typically administeredsystematically may also be used in those cases where the means ofadministration results only in a local effect, rather than systemic.

The dose of local anesthetic will depend on the anesthetic beingadministered as well as the site where the local anesthetic isadministered. For example, in embodiments where the local anesthetic isadministered via a regional block (e.g., an ankle block), the dose ofanesthetic ranges from about 1 ml up to about 30 ml of a 0.5% solution(e.g., bupivacaine). In other embodiments a 3 mg/kg dose (maximum 200mg) of a 2% solution (e.g., lidocaine) can be administered byintr-articular infiltration. In other embodiments the dose of localanesthetic can range between 0.5 ml to about 60 ml of a 0.25% to 5%solution.

Alternatively, phenol can be administered at the site to be treated inplace of (or in addition to) a local anesthetic to anesthesize the area.Phenol can preferably be administered prior to administration of thecapsaicinoid, or can be co-administered with the dose of capsaicinoid.By co-administration it is meant either the administration of a singlecomposition containing both the capsaicinoid and the phenol, or theadministration of the capsaicinoid and the phenol as separatecompositions within short enough time periods that the effective resultis equivalent to that obtained when both compounds are administered as asingle composition.

Prior to the present invention, for example, in U.S. Pat. No. 4,313,958(LaHann), capsaicin is described as producing analgesia whenadministered via “systemic administration” (i.e., intrathecal, epidural,intramuscular, intravenous, intraperitoneal and subcutaneous). Animaltesting was accomplished via “stair-step dosing” which purportedly wassaid to reduce or eliminate some of the side affects of capsaicin. It isreported therein that capsaicin, when systemically delivered in finaldoses of 25 mg/kg or less prior to ultra violet radiation, preventedradiation induced hyperalgesia, but did not elevate the pain thresholdabove normal range. Only when larger doses of capsaicin wereadministered systemically, i.e. final doses of capsaicin being 50 mg/kgor greater, was the pain threshold elevated. LaHann hypothesized (butdid not exemplify), that for clinical use in humans, total doses from0.05 mg/kg to 1,000 mg/kg were acceptable and total doses from 0.25mg/kg to 500 mg/kg were preferred. The rats weighed between 125 and 175grams and the total administered dose of capsaicin ranged from 27 mg/kgto 102 mg/kg (or a total dose injected subcutaneously of about 3.375 mgto about 17.85 mg capsaicin).

More recently, U.S. Pat. No. 5,962,532 (Campbell et al) describes aninjection volume of 0.1 to 20 ml and a concentration of capsaicinbetween 0.01 to 10% for parenteral administration, which calculates to atotal dose of capsaicin of between 0.01 mg to 2,000 mg, based on volumeand concentration.

In contrast, in the present invention, the administration of microgramquantities of capsaicin into discrete localized areas responsible forthe treatment and/or attenuation of pain recognizes significantadvantages over system-wide exposure to milligram quantities in order toproduce a therapeutic effect through alteration of sensory nervefunction in a limited area.

In the present invention, a single dose from about 1 μg to 5,000 μg ofcapsaicin, or a therapeutically equivalent dose of one or more othercapsaicinoids, is administered via injection or implantation to producea selective, highly-localized destruction or incapacitation of C-fiberand/or A-delta-fiber in discrete localized areas responsible for theinitiation of pain for the purpose of eliminating pain arising from thatlocus, while minimizing potential adverse consequences of C-fiber and/orA-delta-fiber activation and/or damage outside of the locus of pain. Incertain preferred embodiments, from about 10 to about 3000 micrograms ofcapsaicin, or a therapeutically equivalent dose of one or more othercapsaicinoids, is administered at the site. In certain preferredembodiments, the amount of capsaicin and/or preferably the range ofcapsaicin administered at the site is from about 100 to about 1000micrograms. In other words, the present invention is directed toadministration of a single dose of capsaicin or other capsaicinoid(s) inan amount that is greatly reduced as compared to the dosage rangepreviously considered useful by those skilled in the art to denervatethe nerve fibers in a discrete, localized area without eliciting asystemic effect (e.g., an effect beyond that discrete, localizedlocation).

Capsaicinoids (capsaicin analogues) with similar physiologicalproperties, i.e., triggering C fiber membrane depolarization by openingof cation channels permeable to calcium and sodium, are known. Forexample, resiniferatoxin is described as a capsaicin analogue in U.S.Pat. No. 5,290,816 to Blumberg. U.S. Pat. No. 4,812,446 to Brand(Procter & Gamble Co.) describes other capsaicin analogues and methodsfor their preparation. U.S. Pat. No. 4,424,205 cites capsaicinanalogues. Ton et al., Brit. J. Pharm. 10:175-182 (1955) discusses thepharmacological actions of capsaicin and its analogues. Capsaicin,capsaicin analogues and other capsaicinoids are also described in detailin WO 96/40079, the disclosure of which is hereby incorporated byreference. Capsaicinoids are also described in EP0 149 545, thedisclosure of which is also hereby incorporated by reference.

Alternatively, capsaicioids (capsaicin analogues) may be administered atthe site in replacement of, part of, or all of the dose of capsaicin,the capsaicin analogue being administered in a therapeuticallyequivalent amount of capsaicin for which it is substituted. Where acapsaicin analogue is selected to replace some or all of the capsaicin,the capsaicin analogue can be selected from those compounds with similarphysiological properties to capsaicin as are known in the art.Resiniferatoxin qualitatively resembles capsaicin in its activity, butdiffers quantitatively in potency (i.e. 10³-10⁴ fold more potent) and inrelative spectrum of actions. For resiniferatoxin it is recommended toadminister 0.1×10⁻³ to 5×10⁻² mg/kg, preferably 0.1×10⁻³ to 5×10⁻³mg/kg, body weight of the subject for single application, or less uponmultiple application. In certain embodiments, resiniferatoxin isadministered in the range of 1×10⁻⁵ mg/kg to 5×10⁻² mg/kg to thesubject. Resiniferatoxin also shows a somewhat different spectrum ofaction, providing greater relief of pain at a given dose. Therefore, thedose of resiniferatoxin should be at least 100 fold less than a dose ofcapsaicin alone.

Other suitable capsaicinoids for use in the present invention include,but are not limited to, N-vanillylnonanamides, N-vanillylsulfonamides,N-vanillylureas, N-vanillylcarbamates, N[(substitutedphenyl)methyl]alkylamides, methylene substituted N[(substitutedphenyl)methyl]alkanamides, N[(substitutedphenyl)methyl]-cis-monosaturated alkenamides, N[(substitutedphenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide,hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin,nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin I, anandamide,piperine, zingerone, warburganal, polygodial, aframodial, cinnamodial,cinnamosmolide, cinnamolide, civamde, nonivamide, olvanil,N-oleyl-homovanillamidia, isovelleral, scalaradial, ancistrodial,β-acaridial, merulidial, scutigeral and any combinations or mixturesthereof.

In certain embodiments, the capsaicinoid utilized in the compositionsand methods of the invention is capsaicin itself. In certain preferredembodiments, the capsaicin is in a purified form obtained from thechemical purification of Capsaicin USP. In certain preferredembodiments, the purified capsaicin used in the compositions and methodsof the invention consists essentially of the trans isomer. Thetrans-isomer of capsaicin has its activity at the vanilloid receptor,and this embodiment, the methods and formulation of the presentinvention are especially useful for treating disorders or pain that canbe alleviated through activation of the vanilloid receptors via, theVR-1 mechanism. Whereas Capsaicin USP contains only about 55-60%trans-capsaicin, with the remainder comprising the precursorsdihydrocapsaicin and nordihydrocapsaicin, in such embodiments theformulation preferably consists essentially of trans-capsaicin, e.g.,preferably having a purity of greater than about 97%, preferably greaterthan about 98%, more preferably greater than about 99% trans-capsaicin.

The trans isomer is preferably prepared in accordance with the methodfor synthesizing the trans isomer of capsaicin from a four step processand purified as describe in U.S. Provisional Application No. 60/461,164filed Apr. 8, 2003, the disclosure of which is hereby incorporated byreference in its entirety. In accordance with U.S. ProvisionalApplication No. 60/461,164 said method for synthesizing the trans isomerof capsaicin comprises a) alkylating 3-methyl butyne with halovalericacid and/or -haloalkanic acid to obtain 8-methyl-6-nonynoic acid and/oralkynoic acid analogues thereof; b) reducing said 8-methyl-6-nonynoicacid to obtain trans-8-methyl-nonenoic acid; c) activating the8-methyl-nonenoic acid to obtain an acid chloride; and d) acylating4-hydroxy-3-methoxybenzylamine hydrochloride with the acid chloride toobtain trans-capsaicin.

In certain embodiments, step a) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)mixing anhydrous tetrahydrofuran (THF) with hexamethylphosphoramide(HMPA) and cooling the mixture to about −78° C. to about −75° C.; ii)adding to the mixture of step i) 3-methyl butyne followed by a dropwiseaddition of a base at a temperature from about −78° C. to about −65° C.to obtain a second mixture; iii) warming the second mixture up to about−30° C. and stirring for about 30 minutes; and iv) adding dropwise asolution of a halovaleric acid in anhydrous tetrahydrofuran at atemperature of about −30° C. for about 10 to about 15 minutes, thengradually warming to room temperature and stirring overnight to obtain areaction mixture.

In certain other embodiments, there is provided a method for obtaining acrude step a) intermediate product further comprising the steps of: i)adding 3M hydrochloric acid (HCl) to a reaction mixture and extractingthe reaction mixture with ethyl acetate; and ii) washing the extractedreaction mixture with brine to yield a crude product.

In certain embodiments, step b) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)dissolving said 8-methyl-6-nonynoic acid in a mixture of anhydroustetrahydrofuran and tertiary-butyl alcohol (t-BuOH) to obtain a solutionand cooling the solution to about −55° C. to about −40° C.; ii)condensing ammonia (NH3) to the solution to a temperature of about −50°C. to about −40° C.; iii) adding sodium drips piece-wise and stirringfrom about 30 minutes to about 2 hours at a temperature from about −45°C. to about −30° C., and iv) adding ammonium chloride (NH4Cl), warmingto room temperature and allowing the NH3 to evaporate overnight toobtain a reaction mixture. Step iii) of the step b) reaction may furthercomprise adding piece-wise lithium and stirring from about 30 minutes toabout 2 hours at a temperature from about −65 C to about −45 C.

In certain other embodiments crude step b) intermediate product furthercomprises the steps of: i) adding water to a reaction mixture; ii)acidifying the reaction mixture with 6N HCl to a pH of about 2 to about3; iii) extracting the reaction mixture with ethyl acetate, washing withbrine and drying over anhydrous sodium sulfate (Na2SO4); and iv)filtering and removing solvents under vacuum to obtain a crude step b)intermediate product.

In certain embodiments, step c) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)adding dropwise a thionyl halide to the 8-methyl-nonenoic acid at roomtemperature for about 15 minutes to about 30 minutes to form a solution;ii) heating the solution at about 50° C. to about 75 C for a period ofabout 1 hour; and iii) removing excess thionyl halide under vacuum atabout 40 C to about 45 C to obtain a step c) intermediate product.

In certain embodiments, step d) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)mixing 4-hydroxy-3-methoxy benzylamine hydrochloride anddimethylformamide (DMF); ii) adding portion-wise at room temperature tothe mixture of step i) 5N sodium hydroxide (NaOH) and stirring for about30 minutes; iii) adding acid halide in anhydrous ether dropwise at atemperature of about 0° C. to about 10° C. for about 20 minutes to about1 hour; and, thereafter, iv) gradually warming the mixture to roomtemperature and stirring overnight. In certain embodiments step d)further comprises the steps of: i) adding water to the mixture andextracting the mixture with ethyl acetate to obtain an ethyl acetateextract; ii) washing said extract with 1N HCl and, thereafter, washingwith sodium bicarbonate (NaHCO3); iii) washing the solution with brineand drying over anhydrous sodium sulfate (Na2SO4); and iv) filtering andremoving solvents under vacuum to obtain a crude product.

In certain preferred embodiments, the method of preparing thetrans-capsaicin or capsaicin intermediate after one or more of the steps(e.g., a), b), c) and/or d)) further comprises purifying the crudeproduct by column chromatography, flash chromatography, or the like,using silica gel and eluting with a mixture of ethyl acetate/hexane toobtain a crude trans-capsaicin product.

Preferably after the capsaicin is formed via the four-step process asdescribed above, the trans-capsaicin product is subjected topurification process comprising the steps of: i) dissolving the crudetrans-capsaicin product in a mixture of ether/hexane and heating themixture to about 40° C. to about 45° C.; ii) cooling the mixture to roomtemperature while stirring for about 2 hours; and iii) filtering themixture to provide a purified trans-capsaicin product.

Alternatively, or additionally to the purification process(es) asdescribed above, the capsaicin is subjected to a further purificationprocess also referred to as a “semi-prep purification” or“semi-preparative purification” of capsaicin. In the semi-preppurification, the capsaicin or previously purified capsaicin is purifiedvia the use of a semi-preparative HPLC (high performance liquidchromatography), which preferably provides for a trans-capsaicin producthaving a purity of greater than about 97%, preferably greater than about98%, more preferably greater than about 99% capsaicin.

In certain preferred embodiments, the active ingredient in thepreparation comprises substantially pure trans-capsaicin (e.g. having nomore than about 10% precursors or other capsaicin compounds such ascis-capsaicin). In more preferred embodiments, the preparation includesat least about 95% pure trans-capsaicin. In most preferred embodiments,the preparation includes at least about 99% pure trans-capsaicin. Whilethe cis-isomer of capsaicin has activity via a number of mechanisms,VR-1 is not considered to comprise a major effect of this agent.

In view of the collective activity of the trans-isomer of capsaicin atthe VR-1 receptor, it is contemplated that it is possible in certainembodiments of the present invention that the amount of trans-capsaicinincluded in the methods and formulations of the present invention willbe reduced in comparison to a preparation which includes a less pureform of capsaicin (e.g., capsaicin USP).

In other embodiments of the present invention, the formulations andmethods of the invention contemplate the use of a capsaicin agentconsisting essentially of cis-capsaicin.

Capsaicin, in either crude extract form, Capsaicin USP, or as purifiedcapsaicin, has been comprehensively studied in a variety of tests invitro, and in several animal species in vivo. Much of the data publishedcan be found in the open scientific literature and in the proprietarystudies discussed below (See: Examples I-XI).

Administration of a single dose of capsaicinoid according to the methodsof the present invention minimizes and/or prevents systemic delivery ofthe capsaicin for the purposes of: a) producing a selective,highly-localized destruction or incapacitation of C-fibers and/orA-delta fibers in a discrete, localized area responsible for theinitiation of pain (e.g., trigger points, intra-articular spaces, bursa)for the purpose of reducing or eliminating pain arising from a discretelocus (i.e., producing antinociception), and b) minimizing potentialadverse consequences of C-fiber and/or A-delta activation and or damageoutside of the locus of pain (i.e., damage to homeostatic mechanisms,such as cardiac reflex [e.g., Bezold-Jarisch reflex] or micturationreflex [e.g., urge to void] or to nerve fibers in the central nervoussystem). The analgesic effect preferably provides pain relief for atleast about 48 to about 120 hours, preferably from about 10 to about 21days, more preferably from about 4 to about 5 weeks, even morepreferably for at least about 6 to about 8 weeks, and most preferablyfor at least about 16 weeks or more.

Delivery systems can also be used to administer capsaicin/capsaicinoidand local anesthetics that produce modality-specific blockade, asreported by Schneider, et al., Anesthesiology, 74:270-281 (1991), orpossess physical-chemical attributes that make them more useful forsustained release then for single injection blockade, as reported byMasters, et al., Soc. Neurosci. Abstr., 18:200 (1992), the teachings ofwhich are incorporated herein. An example of a delivery system includesmicrospheres wherein the anesthetic is incorporated into a polymermatrix in a percent loading of 0.1% to 90% by weight, preferably 5% to75% by weight. It is possible to tailor a system to deliver a specifiedloading and subsequent maintenance dose by manipulating the percent drugincorporated in the polymer and the shape of the matrix, in addition tothe form of local anesthetic (free base versus salt) and the method ofproduction. The amount of drug released per day increasesproportionately with the percentage of drug incorporated into the matrix(for example, from 5 to 10 to 20%). Other forms of delivery systemsinclude microcapsules, slabs, beads, and pellets, which in some casescan also be formulated into a paste or suspension.

The delivery systems are most preferably formed of a syntheticbiodegradable polymer, although other materials may also be used toformulate the delivery systems, including proteins, polysaccharides, andnon-biodegradable synthetic polymers. It is most preferable that thepolymer degrade in vivo over a period of less than a year, with at least50% of the polymer degrading within six months or less. Even morepreferably, the polymer will degrade significantly within a month, withat least 50% of the polymer degrading into non-toxic residues which areremoved by the body, and 100% of the capsaicinoid and anesthetic beingreleased within a two week period. Polymers should also preferablydegrade by hydrolysis by surface erosion, rather than by bulk erosion,so that release is not only sustained but also linear. Polymers whichmeet this criteria include some of the polyanhydrides, poly(hydroxyacids) such as co-polymers of lactic acid and glycolic acid wherein theweight ratio of lactic acid to glycolic acid is no more than 4:1 (i.e.,80% or less lactic acid to 20% or more glycolic acid by weight), andpolyorthoesters containing a catalyst or degradation enhancing compound,for example, containing at least 1% by weight anhydride catalyst such asmaleic anhydride. Other polymers include protein polymers such asgelatin and fibrin and polysaccharides such as hyaluronic acid.Polylactic acid is not useful since it takes at least one year todegrade in vivo. The polymers should be biocompatible. Biocompatibilityis enhanced by recrystallization of either the monomers forming thepolymer and/or the polymer using standard techniques.

Other local carrier or release systems can also be used, for example,the lecithin microdroplets or liposomes of Haynes, et al.,Anesthesiology 63, 490-499 (1985), or the polymer-phospholipidmicroparticles of U.S. Pat. No. 5,188,837 (Domb).

Methods for manufacture of suitable delivery systems for administrationof capsaicinoid alone or together with the local anesthetic are known tothose skilled in the art. The formulations may also be designed todeliver both the anesthetic and the capsaicinoid, either simultaneouslyor sequentially.

The local anesthetic can preferably be administered by direct injection,implantation or infiltration to the site where the capsaicinoid is to beadministered, for example, by administering the local anestheticdirectly in the diseased or pain producing structure or the injurednerve or the nerve that provides inervation to the painful area, or toeffect a regional block of the area including the site where thecapsaicin is to be administered.

In another embodiment, the local anesthetic can preferably beadministered by injection, implantation or infiltration of theanesthetic into the epidural space adjacent to the spine for painoriginating below a patient's waist, or directly into a joint for painoriginating above the patient's waist. The prior administration of aproximal neural block sufficiently desensitizes C fibers to the expectedpungent side effects of the subsequent capsaicinoid administration.

In embodiments where the anesthetic is administered as microspheres, themicrospheres may be injected, implanted or infiltrated through atrochar, or the pellets or slabs may be surgically placed adjacent tonerves, prior to surgery or following repair or washing of a wound. Themicrospheres can be administered alone when they include both thecapsaicin and local anesthetic or in combination with a solutionincluding capsaicin in an amount effective to prolong nerve blockade bythe anesthetic released from the microspheres. The suspensions, pastes,beads, and microparticles will typically include a pharmaceuticallyacceptable liquid carrier for administration to a patient, for example,sterile saline, sterile water, phosphate buffered saline, or othercommon carriers.

The expected side effects of the dose of the capsaicinoid are believedto be from the intense nociceptor discharge occurring during theexcitatory phase before nociceptor desensitization. However, the prioradministration of an anesthetic, such as a nerve block, proximally ordirectly to the site of administration, eliminates or substantiallyreduces such side effects. If some “breakthrough pain” occurs despitethe anesthetic, this pain may be treated by administering an analgesicsuch as a nonsteroidal anti-inflammatory agent or narcotic analgesic(i.e., the various alkaloids of opium, such as morphine, morphine salts,and morphine analogues such as normorphine). The administration of thecapsaicinoid can be repeated if necessary.

The compositions and methods of the present invention can be used fortreating various conditions associated with pain by providing painrelief at a specific site. Examples of conditions to be treated include,but are not limited to, nociceptive pain (pain transmitted across intactneuronal pathways), neuropathic pain (pain caused by damage to neuralstructures), pain from nerve injury (neuromas and neuromas incontinuity), pain from neuralgia (pain originating from disease and/orinflammation of nerves), pain from myalgias (pain originating fromdisease and/or inflammation of muscle), pain associated with painfultrigger points, pain from tumors in soft tissues, pain associated withneurotransmitter-dysregulation syndromes (disruptions inquantity/quality of neurotransmitter molecules associated with signaltransmission in normal nerves) and pain associated with orthopedicdisorders such as conditions of the foot, knee, hip, spine, shoulders,elbow, hand, head and neck.

The receptors involved in pain detection are aptly enough referred to asnociceptor-receptors for noxious stimuli. These nociceptors are freenerve endings that terminate just below the skin as to detect cutaneouspain. Nociceptors are also located in tendons and joints, for detectionof somatic pain and in body organs to detect visceral pain. Painreceptors are very numerous in the skin, hence pain detection here iswell defined and the source of pain can be easily localized. In tendons,joints, and body organs the pain receptors are fewer. The source of paintherefore is not readily localized. Apparently, the number ofnociceptors also influences the duration of the pain felt. Cutaneouspain typically is of short duration, but may be reactivated upon newimpacts, while somatic and visceral pain is of longer duration. It isimportant to note that almost all body tissue is equipped withnociceptors. As explained above, this is an important fact, as pain hasprimary warning functions, for example, impinging on the well-being ofthe patient and thereby causing the patient to seek medical assistance.Nociceptive pain includes, but is not limited to post-operative pain,cluster headaches, dental pain, surgical pain, pain resulting fromsevere burns, post-partum pain, angina, genitor-urinary tract pain, painassociated with sports injuries (tendonitis, bursitis, etc.) and painassociated with joint degeneration and cystitis.

Neuropathic pain generally involves abnormalities in the nerve itself,such as degeneration of the axon or sheath. For example, in certainneuropathies the cells of the myelin sheath and/or Schwann cells may bedysfunctional, degenerative and may die, while the axon remainsunaffected. Alternatively, in certain neuropathies just the axon isdisturbed, and in certain neuropathies the axons and cells of the myelinsheath and/or Schwann cells are involved. Neuropathies may also bedistinguished by the process by which they occur and their location(e.g. arising in the spinal cord and extending outward or vice versa).Direct injury to the nerves as well as many systemic diseases canproduce this condition including AIDS/HIV, Herpes Zoster, syphilis,diabetes, and various autoimmune diseases. Neuropathic pain is oftendescribed as burning, or shooting type of pain, or tingling or itchingpain and may be unrelenting in its intensity and even more debilitatingthan the initial injury or the disease process that induced it.

Neuropathies treatable by the methods of the present invention include:syndromes of acute ascending motor paralysis with variable disturbanceof sensory function; syndromes of subacute sensorimotor paralysis;syndromes of acquired forms of chronic sensorimotor polyneuropathy;syndromes of determined forms of genetic chronic polyneuropathy;syndromes of recurrent or relapsing polyneuropathy; and syndromes ofmononeuropathy or multiple neuropathies (Adams and Victor, Principles ofNeurology, 4th ed., McGraw-Hill Information Services Company, p. 1036,1989). Syndromes of acute ascending motor paralysis are selected fromthe group-consisting of acute idiopathic polyneuritis,Landry-Guillain-Barre Syndrome, acute immune-mediated polyneuritis,infectious mononucleosis polyneuritis, hepatitis polyneuritis; dipthericpolyneuropathy; porphyric polyneuropathy; toxic polyneuropathy (e.g.,thallium); acute axonal polyneuropathy; acute panautonomic neuropathy;vaccinogenic, serogenic, paraneoplastic, polyarteretic and lupuspolyneuropathy.

Syndromes of subacute sensorimotor paralysis are selected from the groupconsisting of deficiency states (e.g., beriberi, pellagra, vitamin B12);heavy metal/industrial solvent poisonings (e.g., arsenic, lead); drugoverdose (e.g., isoniazid, disulfuram, vincristine, taxol,chloramphenicol); uremic polyneuropathy; diabetes; sarcoidosis; ischemicneuropathy and peripheral vascular disease; AIDS; and radiation(radiotherapy). Syndromes of chronic sensorimotor are selected from thegroup consisting of carcinoma, myeloma and other malignancies;paraproteinemias; uremia; beriberi (usually subacute), diabetes,hypo/hyperthyroidism; connective tissue disease; amyloidosis; leprosyand sepsis. Genetic chronic polyneuropathies are selected from the groupconsisting of dominant mutilating sensory neuropathy (adult); recessivemutilating sensory neuropathy (childhood); congenital insensitivity topain; spinocerebellar degenerations, Riley Day Syndrome; UniversalAnesthesia Syndrome; polyneuropathies w/ metabolic disorder; and mixedsensorimotor-autonomic type polyneuropathies. Recurrent/relapsingpolyneuropathy are selected from the group consisting of idiopathicpolyneuritis; porphyria; chronic inflammatory polyradiculoneuropathy;mononeuritis multiplex; beriberi/drug overdose; refsum disease andtangier disease. Mono/multiple neuropathies are selected from the groupconsisting of pressure palsies; traumatic neuropathies (e.g.,irradiationor electrical injury); serum, vaccinogenic (e.g., rabies,smallpox); herpes zoster; neoplastic infiltration; leprosy; dipthereticwound infections;,migrant sensory neuropathy; shingles and post herpeticneuralgia.

Neurotransmitter-dysregulation pain syndromes, rather than involvingabnormal or damaged nerves, result from normal nerves having disruptionsin the quantity and/or quality of the various neurotransmitter moleculesassociated with signal transmission from one neuron to another. Morespecifically, sensory transmitters are released from the afferent nerveending of one nerve cell and received by receptors at the afferent endof another nerve cell. They are chemical messengers which transmit thesignal. There are numerous transmitters, including glutamate, serotonin,dopamine, norepinephrine, somatostatin, substance P, calcitoningene-related peptide, cholecystokinin, opiates and saponins. Alterationsin the quantity of transmitters and neuropeptide release, changes in theafferent receptor, changes of re-uptake of the transmitter and/orneuropeptides can all yield qualitative change of the neural signalingprocess. As a result, the aberrant signal transmission is interpreted bythe body as pain. A representative neurotransmitter dysregulationsyndrome that may be treated by the present invention includesfibromyalgia, which is a common condition characterized by a history ofchronic generalized pain and physical exam evidence of at least 11 of 18defined “tender point” sites in muscles and connective tissue (Wolfe etal., Arthritis Rheum 33:160-72, 1990). Commonly associated conditionsinclude irritable bowel syndrome, headache, irritable bladder syndrome(interstitial cystitis), sleep disturbance, and fatigue (Goldenberg,Current Opinion in Rheumatology 8:113-123, 1996; Moldofsky et al.,Psychosom Med 37:341-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum23:3, 1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981).

A predominant theory regarding the etiology of fibromyalgia holds thatan imbalance and/or dysregulation of neurotransmitter function may occurwithin the central nervous system (CNS), either in the brain or spinalcord and in the relation of the CNS to muscle and connective tissue viaregulatory nerve pathways (Goldenberg, 1996; Russell, Rheum Dis Clin NA15:149-167, 1989; Russell et al., J Rheumatol 19:104-9, 1992; Vaeroy etal., Pain 32:21-6, 1988; Wolfe et al., 1996). Neurotransmitters arechemical messengers, amino acids, biogenic amines and neuropeptides,emitted from nerve cells that interact with receptors on other nervecells, as well as other cell types, including muscle and immune cells.Neurotransmitter imbalance, which leads to increased pain experience,may include a qualitative and/or quantitative decrease in the functionof such neurotransmitters as glutamate, serotonin, dopamine,norepinephrine, somatostatin, substance P, calcitonin gene-relatedpeptide, cholecystokinin, opiates and saponins. Fibromyalgia ischaracterized by a relative deficit of serotonin effect and relativeexcess of substance P effect. This imbalance results in amplifiedmodulation of pain-signaling in the central nervous system, resulting inneurogenic pain (Matucci-Cerinic, Rheumatic Disease Clinics of NorthAmerica 19:975-991, 1993; Bonica, The Management of pain, Lea andFebiger, 2d ed., Philadelphia, pp. 95-121, 1990). Similar mechanisms maybe at work to cause associated conditions; for example, dysregulation ofneurotransmitter signaling in the bowel musculature, leading toirritable bowel syndrome symptoms such as cramping, diarrhea, and/orconstipation.

Neurotransmitter-dysregulation pain syndromes include, but are riotlimited to the following: generalized syndromes, localized syndromes;craniofascial pain; vascular disease; rectal, perineum and externalgenitalia pain; and local syndromes of the leg/foot.

Generalized syndromes are selected from the group consisting of stumppain, causalgia, reflex sympathetic dystrophy, fibromyalgia or diffusemyofascial pain and burns. Localized syndromes are selected from thegroup consisting of trigeminal neuralgia; acute herpes zoster;panautonomic neuralgia; geniculate neuralgia (Romsay Hunt Syndrome);glossopharyngeal neuralgia; vagus nerve neuralgia and occipitalneuralgia. Craniofacial pain includes temporomandibular pain.Suboccipital and cervical muskuloskeletal disorders are selected fromthe group consisting of myofascial syndrome, which includes cervicalsprain cervical hyperextension (whiplash); stemocleidomastoid muscle;trapezius muscle; and stylohyoid process syndrome (Eagle's syndrome).Vascular disease is selected from the group consisting of Raynaud'sdisease; Raynaud's phenomenon; frosbite; erythema pernio (chilblains);acrocyanosis and livedo reticularis. Rectal, perineum and externalgenitalia pain are selected from the group consisting of iliohypogastricneuralgia; iliolinguinal nerve; genotifemoral nerve and testicular pain.Local syndromes of the leg/foot are selected from the group consistingof lateral cutaneous neuropathy (neuralgia paresthetica);oobturatorneuralgia; femoral neuralgia; sciatica neuralgia; interdigital neuralgiaof the foot (Morton's metatarsalgia or neurma); injection neuropathy andpainful legs and moving toes.

Pain Intensity assessment scales are typically used by those of ordinaryskill in the art to evaluate analgesic choices and therapeutic effects.

A Visual Analogue Scale (VAS) is a measurement instrument that measuresa characteristic that is believed to range across a continuum of valuesand cannot easily be directly measured. For example, the amount of painthat a patient feels ranges across a continuum from none to an extremeamount of pain may be indirectly measured via the use of a VAS.Operationally a VAS is usually a horizontal line, 100 mm in length,anchored by word descriptors at each end, for example “no pain” at oneend and “very severe pain” at the other end. The patient, marks on theline the point that they feel represents their perception of theircurrent state. The VAS score is determined by measuring in millimetersfrom the left hand end of the line to the point that the patient marks.The 100-mm visual analog scale (VAS), a unidimensional scale that isversatile and easy to use, has been adopted in many settings.

The capsaicinoid formulations and methods described herein may be usedto treat many conditions where the capsaicinoid can be administered viainjection or implantation through the skin of the patient, including butnot limited to the treatment of acute or chronic pain, nociceptive andneuropathic pain, pre- and post-operative pain, cancer pain, painassociated with neurotransmitter dysregulation syndromes and orthopedicdisorders, sports-related injuries, acute traumatic pain, nociceptivepain, and neurotransmitter-dysregulation syndromes.

Treatment of Chronic Post-Herniorrhaphy Pain

In a preferred embodiment, the capsaicinoid formulations and methodsdisclosed herein can be used for the treatment/attenuation of chronicpost-herniorrhaphy pain. Chronic post-herniorrhaphy pain occurs inbetween 5-30% of patients, with social consequences limiting some typeof activity in about 10% of patients and 1-4% of patients are referredto chronic pain clinics. Nerve damage is probably the most plausiblepathogenic factor, but specific principles for therapy have not beenevidence-based and range from usual analgesics to re-operation with meshremoval and various types of nerve sections without any demonstratedefficacy in sufficient follow-up studies with or without randomizeddata. In patients suffering from pain associated with chronicpost-herniorrhaphy, the dose of capsaicinoid can be administered to thesite where the surgery was performed or to the immediate areasurrounding the incision.

Treatment of Pain Associated with Morton's Neuroma

In another preferred embodiment, the capsaicinoid formulations andmethods disclosed herein can be used for the treatment/attenuation ofpain associated with Morton's Neuroma. Morton's Neuroma is considered tobe most likely a mechanically induced degenerative neuropathy which hasa strong predilection for the third common digital nerve in middle-agedwomen. It is considered a well-defined model of neuropathic pain. Theusual medical treatment of Morton's neuroma includes local injection ofsteroids, often with lidocaine. When nonsurgical means fail to relievepatient's symptoms, surgical removal of this offending neuroma through adorsal approach can produce dramatic relief of symptoms in approximately80% of patients. However, 20% of patients experience neuroma recurrence(referred to as stump or amputation neuroma) that often causes moresevere pain that the original neuroma and is generally treatmentresistant. Administration of capsaicinoid in accordance with theinvention is useful for the treatment of the neuropathic pain associatedwith Morton's Neuroma and may reduce the re-occurrence of painassociated with stump or amputation neuroma.

Orthopedic Disorders

The capsaicinoid formulations and methods disclosed herein may beutilized to treat/attenuate pain associated with orthopedic disorders.Orthopedic disorders treatable via the use of the formulations andmethods of the invention include but are not limited to disorders of theknee, shoulders, back, hip, spine, elbows, foot, hand and otherdisorders, which involve pain at a specific site or body space.Orthopedic disorders affecting these locations include, but are notlimited to bursitis, tendonitis, osteoarthritis, and rheumatoidarthritis. Bursitis is the inflammation of a bursa. Bursae are saclikecavities or potential cavities that contain synovial fluid located attissue sites where friction occurs (e.g., where tendons or muscles passover bony prominences). Bursae facilitate normal movement, minimizefriction between moving parts, and may communicate with joints. In thenormal state, the bursa provides a slippery surface that has almost nofriction. A problem arises when a bursa becomes inflamed. The bursaloses its gliding capabilities, and becomes more and more irritated whenit is moved. When the condition called bursitis occurs, the slipperybursa sac becomes swollen and inflamed. The added bulk of the swollenbursa causes more friction within already confined spaces. Also, thesmooth gliding bursa becomes gritty and rough. Movement of an inflamedbursa are painful and irritating. Bursitis usually occurs in theshoulder (subacromial or subdeltoid bursitis). Other sites include theolecranon (miners' elbow), prepatellar (housemaid's knee) orsuprapatellar, retrocalcaneal (Achilles), iliopectineal (iliopsoas) ofthe hip, ischial (tailor's or weaver's bottom) of the pelvis, greatertrochanteric of the femur, and first metatarsal head (bunion). Bursitismay be caused by trauma, chronic overuse, inflammatory arthritis (eg,gout, rheumatoid arthritis), or acute or chronic infection (eg, pyogenicorganisms, particularly Staphylococcus aureus; tuberculous organisms;which now rarely cause bursitis). Orthopedic disorders of the footinclude, but are not limited to, heel spurs, corns, bunions, Morton'sneuroma, hammertoes, ankle sprain, fractures of the ankle or metatarsalsor sesamoid bone or toes, plantar fascitis and injuries to the achillestendon. Orthopedic disorders of the hand include, but are not limitedto, arthritis, carpal tunnel syndrome, ganglion cysts, tendon problemssuch as lateral epicondylitis, medial epicondylitis, rotator cufftendonitis, DeQuervian's tenosynovitis, and trigger finger/triggerthumb. Other orthopedic disorders include, but are not limited to,Paget's disease, scoliosis, soft-tissue injuries such as contusions,sprains and strains, long bone fractures and various other sportsinjuries some of which include patellar tendonitis and lumbar strain.

Treatment of non-infected acute bursitis has mainly consisted oftemporary rest or immobilization and high-dose NSAIDs, sometimesnarcotic analgesics, may be helpful. Voluntary movement should beincreased as pain subsides. Pendulum exercises are particularly helpfulfor the shoulder joint. Aspiration and intrabursal injection of depotcorticosteroids 0.5 to 1 ml (triamcinolone diacetate 25 or 40 mg/ml)mixed with at least 3 to 5 ml of local anesthetic after infiltrationwith 1% local anesthetic (e.g., lidocaine) is the treatment of choicewhen rest alone is inadequate. The depot corticosteroid dose and volumeof mixture are gauged to the size of the bursa. Reaspiration andinjection may be required with resistant inflammation. Systemiccorticosteroids (prednisone 15 to 30 mg/day or equivalent for 3 days)are occasionally indicated in resistant acute cases after infection andgout have been excluded. Chronic bursitis is treated as acute bursitis,except that splinting and rest are less likely to be helpful. Surgery israrely needed to treat bursitis and is usually done only in the chroniccases that have not improved with traditional therapy. The most commonsurgical treatment, if needed, is an Incision and Drainage (called an Iand D) and is used only in cases of infected bursa. The surgeon firstnumbs the skin with an anesthetic and then opens the bursa with ascalpel. Finally, the surgeon drains the fluid present in the inflamedbursa. Sometimes it is necessary to excise the entire bursa surgically.This is indicated only if the bursal swelling causes problems.

The capsaicinoid may be administered via injection in a location andfashion similar to that currently utilized with respect to localizedinjections of corticosteroids. For example, in certain embodiments, thedose of capsaicinoid is administered by intra-articular injection intothe bursa.

Tendonitis

The capsaicinoid formulations and methods disclosed herein may beutilized to treat/attenuate pain associated with tendonitis(inflammation of the tendons). When tendons become inflamed, the actionof pulling the muscle becomes irritating and painful. The cause is oftenunknown. Most instances tendonitis occurs in middle-aged or olderpersons as the vascularity of tendons attenuates; repetitive microtraumamay increase injury. Repeated or extreme trauma (short of rupture),strain, or excessive (unaccustomed) exercise is most frequentlyimplicated. The most common cause of tendonitis is overuse. Commonly,individuals begin an exercise program, or increase their level ofexercise, and begin to experience symptoms of tendonitis. The tendon isunaccustomed to the new level of demand, and this overuse will cause aninflammation and tendonitis. Tendonitis produces pain, tenderness andstiffness near a joint which is aggravated by movement.

General practitioners commonly use non-steroidal anti-inflammatorydrugs. (NSAIDs) to treat tennis elbow, but there are no trials to datethat have compared them with other painkillers and one study found noclinically important benefit over placebo. Symptomatic relief isprovided by rest or immobilization (splint or cast) of the tendon,application of heat for chronic inflammation or cold for acuteinflammation (whichever benefits the patient should be used), localanalgesic drugs, and NSAIDs for 7 to 10 days. A critical review of therole of various anti-inflammatory medications in tendon disorders foundlimited evidence of short-term pain relief and no evidence of theireffectiveness in providing even medium term clinical resolution. Use ofcorticosteroid injections provides mixed results in relief of pain andat times insufficient evidence to support their use. Injection of thetendon sheath with a depot corticosteroid (eg, dexamethasone acetate,methylprednisolone acetate, hydrocortisone acetate) 0.5 to 1 mL mixedwith an equal or double volume of 1% local anesthetic (eg, lidocaine)has been utilized as a treatment, depending on severity and site. Theinjection is made blindly or proximal to the site of maximum tendernessif the specific inflammation site cannot be identified. Particular careshould be taken not to inject the tendon per se (which offers greaterresistance) because it may be weakened and rupture in active persons.Reexamination of a less inflamed site 3 or 4 days later often disclosesthe specific lesion, and a second injection can be made with greaterprecision. Rest of the injected part is advisable to diminish risk oftendon rupture. Although complications associated with intrarticular andsoft tissue steroid injection are relatively uncommon, when acomplication does occur, it can result in severe and disablingconsequences for the subject. A small proportion of subjects fail torespond to only one injection of corticosteroid and some subjects whoinitially improve at four weeks had worst symptoms by six months.Therefore with this lack of consensus, no good evidence to support theuse of local corticosteroid injections and the unknown long-termside-effects of using steroids, an alternative treatment must be sought.

In one embodiment of the present invention, pain associated withtendonitis of the knee, shoulders, hip, pelvis, spine, elbows, leg andfoot is treated with a capsaicinoid injection undertaken in similarfashion as a localized corticosteroid injection. For example, inembodiments where the capsaicinoid formulation is used for thetreatment/attenuation of pain associated with tendonitis or bursitis ofthe shoulder, the dose of capsaicinoid can be administered by injectioninto the subacromial bursa with the needle inserted into the spacebetween the acromium and the humerus on the lateral aspect of theshoulder.

Osteoarthritis

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with osteoarthritis (degenerativejoint disease). Osteoarthritis is characterized by the breakdown of thejoint's cartilage. Cartilage is the part of the joint that cushions theends of bones. Cartilage breakdown causes bones to rub against eachother, causing pain and loss of movement. Most commonly affectingmiddle-aged and older people, osteoarthritis can range from very mild tovery severe. It affects hands and weight-bearing joints such as knees,hips, feet and the back. There are many factors that can causeosteoarthritis, including but not limited to age, genetics, obesity,sports-related activities, work-related activities, or accidents.Treatment of osteoarthritis focuses on decreasing pain and improvingjoint movement, and may include: Exercises to keep joints flexible andimprove muscle strength; Many different medications are used to controlpain, including corticosteroids and NSAIDs, glucocorticoids injectedinto joints that are inflamed and not responsive to NSAIDS. For mildpain without inflammation, acetaminophen may be used; heat/cold therapyfor temporary pain relief, joint protection to prevent strain or stresson painful joints; surgery (sometimes) to relieve chronic pain indamaged joints; and weight control to prevent extra stress onweight-bearing joints.

Pain associated with osteoarthritis may be treated/attenuated with thecapsaicinoid formulations administered, e.g., by intra-articularinjection at the affected site, including but not limited to orthopedicdisorders of the knee such as osteoarthritis, shin splints, medialtibial stress syndrome, bursitis, tendonitis (patellar tendinitis);tears of the anterior cruciate ligament (blown out knee), posteriorcruciate ligament, medial collateral ligament and lateral collateralligament; arthritis of the knee; meniscal cartilage tear; Runner'sconditions such as iliotibial band syndrome and Pes Anserine bursitis;torn meniscus and limited cartilage defects of the knee; orthopedicdisorders of the shoulders including, but not limited to, bursitis,dislocation, separation, impingement and tear of the rotator cuff,tendonitis, adhesive capsulitis (frozen shoulder) and fractures.

Rheumatoid Arthritis

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with rheumatoid arthritis. Rheumatoidarthritis is a chronic, systemic, inflammatory disease that chieflyaffects the synovial membranes of multiple joints in the body. Becausethe disease is systemic, there are many extra-articular features of thedisease as well. Rheumatoid Arthritis can affect many joints in thebody, including the knee, ankle, elbow, and wrist. Joints that areactively involved with the disease are usually tender, swollen, andlikely demonstrate reduced motion. The disease is considered anautoimmune disease that is acquired and in which genetic factors appearto play a role. The capsaicinoid may be administered via intra-articularinjection in a location and fashion similar to that currently utilizedwith respect to localized injections of corticosteroids.

There are several different classes of drugs utilized to treat patientswith the various types of rheumatic disease which maybe used in additionto the capsaicinoid treatment described herein, including analgesics tocontrol pain, corticosteroids, uric acid-lowering drugs,immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, anddisease-modifying antirheumatic drugs.

Back Pain

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with back pain. Back pain is thesecond most common reason for doctor visits in the U.S. The causes oflower back pain are numerous. Some of the more common causes of lowerback pain are: sudden injury to the back such as may occur in an autoaccident, fall, sports, or other manner; gynecological conditions suchas endometriosis, menstrual cramps, fibroid tumors, and pregnancy aresometimes the cause of lower back pain in women; and stress to themuscles, nerves, or ligaments in the lower back. Slipped discs, pinchednerves, sciatica, aging, and infections are other common causes of lowerback pain. The treatment of lumbar strain consists of resting the back(to avoid re-injury), medications to relieve pain and muscle spasm,local heat applications, massage, and eventual (after the acute episoderesolves) reconditioning exercises to strengthen the low back andabdominal muscles Zygapophysial joints, better known as facet or “Z”joints, are located on the back (posterior) of the spine on each side ofthe vertebrae where it overlaps the neighboring vertebrae. The facetjoints provide stability and give the spine the ability to bend andtwist. They are made up of the two surfaces of the adjacent vertebrae,which are separated by a thin layer of cartilage. The joint issurrounded by a sac-like capsule and is filled with synovial fluid (alubricating liquid that reduces the friction between the two bonesurfaces when the spine moves and also nourishes the cartilage.) Aproblem (such as inflammation, irritation, swelling or arthritis) in thefacet joint may cause low back pain. Diagnostic tests can show anabnormality in a facet joint, which may suggest that the facet joint isthe source of the pain. However, sometimes normal study results can bepresent while the facet joint is still the source of pain, and abnormalresults do not always implicate the facet joint.

To determine if a facet joint is truly the source of back pain, aninjection of local anesthetic (.e.g, as a block) may be utilized. If aninjection of a small amount of anesthetic or numbing medication into thefacet joint reduces or removes the pain, it indicates that the facetjoint may be the source of the pain. This is diagnostic use of the facetjoint injection. Once a facet joint is pinpointed as a source of pain,therapeutic injections of anesthetic agents and anti-inflammatorymedications may give pain relief for longer periods of time. Thecapsaicinoid formulations may be administered in such situations toattenuate such pain.

Facet joint injections are performed while the patient is awake, under alocal anesthetic, and able to communicate. Sometimes, the health careprovider may also administer drugs to make the patient more comfortableduring the procedure. The injection is usually performed while thepatient is lying on his or her stomach on an X-ray table. EKG, bloodpressure cuffs and blood-oxygen monitoring devices may be hooked upprior to the injection process. Once the proper site has beendetermined, the physician will inject the anesthetic (often lidocaine orbupivicaine) and the anti-inflammatory (usually a corticosteroid.). Thisprocess may then be repeated depending on the number of affected facetjoints.

The capsaicinoid may be administered via injection to treat back pain,e.g., in a location and fashion similar to that currently utilized withrespect to localized injections of corticosteroids.

Heel Spur

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with a heel spur, which is aprojection or growth of bone where certain muscles and soft tissuestructures of the foot attach to the bottom of the heel. Most commonly,the plantar fascia, a broad, ligament-like structure extending from theheel bone to the base of the toes becomes inflamed, and symptoms of heelpain begin. As this inflammation continues over a period of time, withor without treatment, a heel spur is likely to form. If heel pain istreated early, conservative therapy is often successful arid surgery isusually avoided. Early signs of heel pain are usually due to plantarfasciitis, the inflammation of the plantar fascia. It is probably themost common cause of heel pain seen by the podiatrist. It is seen in allgroups of people; runners, athletes, week-end warriors, people who havejobs requiring a fair amount of standing, walking, or lifting, and thosewho have recently gained weight. Initially, patients receive taping ofthe foot and when indicated, cortisone injections or a short course ananti-inflammatory medication, taken orally. Exercises, night splints,and physical therapy are used as adjunct methods to try to reduce theinflammation. If successful, a custom made in shoe orthotic is made tocontrol the abnormal stress and strain on the plantar fascia resultingin remission of the majority of the symptoms.

When capsaicinoid is used for the treatment of plantar fascia, the doseof capsaicinoid is preferably administered by injection into theaffected area. When surgery is required, the capsaicinoid is preferablyadministered by infiltration into the heel bone.

Laparoscopic Cholecystectomy

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with laparoscopic cholecystectomy.Laparoscopic cholecystectomies have virtually replaced open surgicalcholecystectomy. However, patients undergoing laparoscopiccholecystectomies still have pain. Pain control following surgerytypically includes use of opioids, especially within the first severaldays after surgery. The administration of capsaicinoid in a patient whohas undergone a laparoscopic cholecystectomy may reduce the amount ofopioid consumption and postoperative pain scores associated with theprocedure. In patients suffering from pain associated with alaparoscopic cholecystectomy, the dose of capsaicinoid can beadministered either by injection, infiltration or both injection andinfiltration. When the dose of capsaicinoid is administered byinjection, the capsaicinoid may be injected directly the site ofincision or to the immediate area surrounding the surgical site.

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with other laparoscopic surgicalprocedures, as well.

Dose

In preferred embodiments of the present invention; the dose ofcapsaicinoid contained in a unit dose injection/implantation is fromabout 1 μg to about 5000 μg of capsaicin, preferably from about 10 μg toabout 3000 μg capsaicin, more, preferably from about 300 μg to about1500 μg capsaicin, or a therapeutically equivalent amount of one or morecapsaicinoids. In certain preferred embodiments, the dose of capsaicinis from about 400 μg to about 1200 μg, or a therapeutically equivalentamount of one or more capsaicinoids. Preferably, the capsaicinoid isadministered in a pharmaceutically and physiologically acceptablevehicle for injection or implantation.

In certain other embodiments, suitable doses of capsaicin/capsaicinoidfor injection or implantation for the treatment of nociceptive pain,neuropathic pain, pain from nerve injury, pain from myalgias, painassociated with painful trigger points, pain from tumors in softtissues, pain associated with neurotransmitter-dysregulation syndromesand pain associated with orthopedic disorders range from about 1 μg toabout 3000 μg of capsaicin (trans 8-methyl-N-vanillyl-6-noneamide),preferably from about 20 to about 300 micrograms, more preferably fromabout 35 to 200 micrograms, with 100 μg most preferred.

In certain preferred embodiments, an injection of local anesthetic canbe administered in proximity to the site prior to administration of thecapsaicinoid, e.g., as described above and in the appended examples. Inother embodiments, phenol can be used instead of or in addition to thelocal anesthetic.

Injectable/Implantable Formulations

In embodiments where the capsaicinoid is administered by injection, thecapsaicinoid is administered to a discrete site by penetrating the outerlayer of the skin with an instrument known to those skilled in the artfor administering injections, e.g., a needle and syringe.

The dose of capsaicinoid is preferably prepared forinjection/implantation by being incorporated into a pharmaceutically andphysiologically acceptable vehicle for administration through the skinof the patient (e.g., human or animal). For example, the capsaicinoidmay be dissolved in oils, propyleneglycol or other solvents commonlyused to prepare injectable or implantable solutions. Suitablepharmaceutically acceptable vehicles preferably include aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, suspending and dispersing agents, emulsifyingagents, sequestering or chelating agents and any combinations ormixtures thereof. Examples of aqueous vehicles preferably include SodiumChloride Injection, Bacteriostatic Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Bacteriostatic Sterile Water Injection, Dextrose Lactated RingersInjection and any combinations or mixtures thereof. Nonaqueousparenteral vehicles preferably include fixed oils of vegetable origin,cottonseed oil, corn oil, sesame oil, peanut oil and any combinations ormixtures thereof. Antimicrobial agents in bacteriostatic or fungistaticconcentrations preferably include phenols, cresols, mercurials, benzylalcohol, chlorobutanol, ethyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride benzethonium chloride and mixturesthereof. Isotonic agents preferably include sodium chloride, dextroseand any combinations or mixtures thereof. Buffers preferably includeacetate, phosphate, citrate and any combinations or mixtures thereof.Antioxidants preferably include ascorbic acid, sodium bisulfate and anycombinations or mixtures thereof. Suspending and dispersing agentspreferably include sodium carboxymethylcelluose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and any combinations or mixturesthereof. Emulsifying agents preferably include Polysorbate 80 (Tween80). Sequestering or chelating agents of metal ions preferably includeethylenediaminetetraacetic acid. Additional pharmaceutically acceptablevehicles also preferably include ethyl alcohol, polyethylene glycol,glycerin and propylene glycol for water miscible vehicles and sodiumhydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment and any combinations or mixtures thereof.

Depending on the pharmaceutically acceptable vehicle chosen, the dose ofcapsaicinoid can be administered as an aqueous solution or suspensionfor injection or implantation. Injections are separated into fivedistinct types, generally classified as (i) medicaments or solutions oremulsions suitable for injection; (ii) dry solids or liquid concentratescontaining no buffers, diluents, or other added substances, and whichupon the addition of suitable vehicles, yield solutions conforming inall aspects to the requirements for injections; (iii) preparations asdescribed in (ii) except that they contain one or more buffers, diluentsor other added substances; (iv) solids which are suspended in a suitablefluid medium and which are not to be injected intravenously or into thespinal canal; and (v) dry solids, which upon the addition of suitablevehicles, yield preparations conforming in all respects to therequirements of Sterile Suspensions (see: H. C. Ansel, Introduction toPharmaceutical Dosage Forms, 4th Edit., 1985, pg. 238).

In certain other embodiments, a surfactant can preferably be combinedwith one or more of the pharmaceutically acceptable vehicles previouslydescribed herein so that the surfactant or buffering agent prevents theinitial stinging or burning discomfort associated with capsaicinoidadministration, as a wetting agent, emulsifier, solubilizer and/orantimicrobial.

Suitable surfactants include, but are not limited to, sodium stearylfumarate, diethanolamine cetyl sulfate, polyethylene glycol,isostearate, polyethoxylated castor oil, benzalkonium chloride, nonoxyl10, octoxynol 9, polyoxyethylene sorbitan fatty acids (polysorbate 20,40, 60 and 80), sodium lauryl sulfate, sorbitan esters (sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitantristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate,sorbitan stearate, sorbitan dioleate, sorbitan sesqui-isostearate,sorbitan sesquistearate, sorbitan tri-isostearate),-lecithinpharmaceutical acceptable salts thereof and combinations thereof. Whenone or more surfactants are utilized in the formulations of theinvention, they may be combined, e.g., with a pharmaceuticallyacceptable vehicle and may be present in the final formulation, e.g., inan amount ranging from about 0.1% to about 20%, more preferably fromabout 0.5% to about 10%.

Buffering agents may also be used to provide drug stability; to controlthe therapeutic activity of the drug substance (Ansel, Howard C.,“Introduction to Pharmaceutical Dosage Forms,” 4^(th) Ed., 1985); and/orto prevent the initial stinging or burning discomfort associated withcapsaicin administration. Suitable buffers include, but are not limitedto sodium bicarbonate, sodium citrate, citric acid, sodium phosphate,pharmaceutically acceptable salts thereof and combinations thereof. Whenone or more buffers are utilized in the formulations of the invention,they may be combined, e.g., with a pharmaceutically acceptable vehicleand may be present in the final formulation, e.g., in an amount rangingfrom about 0.1% to about 20%, more preferably from about 0.5% to about10%.

In certain preferred embodiments, the pharmaceutical vehicle utilized todeliver the injectable capsaicinoid comprises about 20% PEG 300, about10 mM histidine and about 5% sucrose in water for injection.

In other preferred embodiments, delivery systems can be used toadminister a unit dose of capsaicinoid. The dose of capsaicinoid canpreferably be administered as injectable or implantable microparticles(microcapsules and microspheres). The microparticles are preferably in asize and distribution range suitable for implantation or injection. Thediameter and shape of the microparticles can be manipulated to modifythe release characteristics. For example, larger diameter microparticleswill typically provide slower rates of release and reduced tissuepenetration and smaller diameters of microparticles will produce theopposite effects, relative to microparticles of different mean diameter,but of the same composition. In addition, other particle shapes, such ascylindrical shapes, can also modify release rates by virtue of theincreased ratio of surface area to mass inherent to such alternativegeometrical shapes, relative to a spherical shape. The diameter ofmicroparticles preferably range in size from about 5 microns to about200 microns in diameter.

In a more preferred embodiment, the microparticles range in diameterfrom about 20 to about 120 microns. In another embodiment of the presentinvention, the dose of capsaicinoid can be administered in the form ofimplantable pellets, rods and slabs. Methods for manufacture ofmicroparticles, pellets, rods and slabs are well known in the art andinclude solvent evaporation, phase separation and fluidized bed coating.

When the preferred methods of the present invention provide foradministration of a single dose of capsaicinoid alone, the single doseof capsaicin is preferably administered at a discrete site in an amounteffective to denervate the discrete site without eliciting an effectoutside the discrete location. The single dose is preferablyadministered in a nerve directly at the site where pain relief isneeded, directly into the pain producing structure, or into a nerve thatprovides inervation to the painful area via injection or implantation.Injectable or implantable administration preferably includes, but is notlimited to subcutaneous (under the skin), intramuscular (muscle),itrathecal, epidural, intraperitoneal, caudal, intradermal orintracutaneous (into the skin), intercostals at a single nerve,intra-articular (joints) or body spaces, intrasynovial (joint fluid),intraspinal (spinal column), intra-arterial (arteries) administrationsand administration into other connective tissue compartments. As usedherein “intraspinal” means into or within the epidural space, theintrathecal space, the white or gray matter of the spinal cordaffiliated structures such as the dorsal root and dorsal root ganglia.

Examples of intra-articular administration include knee, elbow, hip,sternoclavicular, tempromandibular, carpal, tarsal, wrist, ankle,intervertebral disk, ligamentum flavum and any other joints subject toarthritic conditions. Examples of body spaces include pleura,peritoneium, cranium, mediastinum, pericardium, and bursae or bursal.Examples of bursae include acromial, bicipitoradial, cubitoradial,deltoid, infrapatellar, ishchiadica, and other bursa known to thoseskilled in the art to be subject to pain.

When the single dose of capsaicin is administered via injection, theinjection volume of capsaicin will depend on the localized site ofadministration. Suitable injection volumes to be delivered preferablyrange from about 0.1 to about 20 ml, more preferably from about 0.5 toabout 10 ml and most preferably from about 1.0 to about 5 ml, dependingon the site to be treated.

The administration of the anesthetic along with the subsequentadministration of the capsaicinoid formulations and methods of theinvention alleviate or attenaute pain at the site for a prolonged periodof time. With respect to joint pain, in certain preferred embodiments asingle unit dose capsaicinoid injection or implantation attenuates painat the site for at least about one month, more preferably at least about3 months, and typically in certain embodiments from about 3 to about 6months. With respect to pain associated with arthritic conditions suchas osteoarthritis, in certain preferred embodiments a single unit dosecapsaicinoid injection or implantation attenuates pain at the site forat least about 3 months to at least about 4 months. With respect topost-surgical pain, in certain preferred embodiments a single unit dosecapsaicinoid injection or implantation attenuates pain at the site forat least about one week, and in certain embodiments for at least about 1month. Patients can be monitored for pain relief and increased movement,in the situation where treatment is in a joint. The treatment can berepeated as necessary to control the symptoms.

Breakthrough Pain

The term “breakthrough pain” means pain which the patient experiencesdespite the fact that the patient is being or was administered generallyeffective amounts of, e.g., capsaicin. In conjunction with the use ofthe capsaicinoid formulations and methods described herein, it iscontemplated that it is nonetheless possible that the patient willexperience breakthrough pain. For the treatment of breakthrough pain,the individual may be further administered an effective amount of ananalgesic in accordance with the treatment of pain in such situationsperformed by those skilled in the art. The analgesic may be any known tothe person skilled in the art such as those selected from the groupcomprising gold compounds such as sodium aurothiomalate; non-steroidalanti-inflammatory drugs (NSAIDs) such as naproxen, diclofenac,flurbiprofen, ibuprofen ketoprofen, ketorolac, pharmaceuticallyacceptable salts thereof and the like; opioid analgesics such ascodeine, dextropropoxyphene, dihydrocodeine, morphine, diamorphine,hydromorphone, hydrocodone, methadone, pethidine, oxycodone,levorphanol, fentanyl and alfentanil, para- aminophenol derivatives suchas paracetamol, pharmaceutically acceptable salts thereof and the like;and salicylates such as aspirin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE IOsteoarthritis of the Knee Safety Study

The following clinical study was carried out in order to evaluate thesafety, tolerability, systemic pharmacokinetics, and efficacy ofpurified capsaicin administered by intra-articular infiltration togetherwith a local anesthetic administered by intra-articular infiltration insubjects with osteoarthritis of the knee.

The primary objective of the study was to evaluate the safety andtolerability of intra-articular capsaicin, when co-administered withintra-articular local anesthetic, compared to placebo, in subjects withend-stage osteoarthritis of the knee, already scheduled to receive kneereplacements.

Purified capsaicin was supplied in vials containing 5 mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug was stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle was used to dilute the drug to final concentrationsof purified capsaicin, as follows: TABLE 1 Dose Level ConcentrationTotal Volume of Dose  10 μg  2 μg/mL 5 mL 100 μg 20 μg/mL 5 mL 300 μg 60μg/mL 5 mL

Each vial was used for one infiltration administration only andappropriately labeled. The supplier of the purified capsaicin wasFormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vialswere supplied in bulk to the study center with each vial labeledaccording to the contents of the vial. The Pharmacist/Study Nurse, whoprepared the injection, maintained the investigational product in alockable cabinet at the required temperature, 15-25° C. The study blindwas maintained by the Pharmacist/Study Nurse.

Placebo vehicle for purified capsaicin was supplied in vials containing5 mL. Local anesthetic (Lignocaine 2%) was used for each intra-articularinfiltration.

The study was a single center, randomized, double blind, placebocontrolled, dose ranging Phase 1 study of three dose levels (10 μg, 100μg, or 300 μg) of intra-articularly administered purified capsaicin,when co-administered with intra-articular local anesthetic, in subjectswith osteoarthritis of the knee who were scheduled to undergo total kneereplacement. The doses of purified capsaicin used in this trial werewell below (>100 fold) doses known to be toxic to animals. The study wasdesigned to include 16 evaluation subjects. Sixteen subjects wereenrolled in the study; 12 were treated with ultra-purified capsaicin (4each with 10, 100, and 300 μg doses) and 4 were treated with placebovehicle. Sixteen subjects completed the study.

Patients were treated randomly and in double-blind fashion in fourtreatment cohorts, with each cohort having a progressively longerinterval between the intra-articular administration of study medicationand subsequent total knee replacement (2, 4, 7, and 14 days). Foursubjects, 1 in each of the 4 dose groups (placebo, 10 μg, 100 μg, and300 μg of capsaicin), were enrolled in each treatment cohort. Gross andmicroscopic pathology analysis was completed for each treatment cohortbefore the next treatment cohort was treated.

Each subject had 3 study visits: a Screening Day (Day −7 to −1), theTreatment Day (Day 0), and a Post-Treatment Day (scheduled for Day +2,+4, +7, or +14). On the Treatment Day the subject was randomized,pre-treatment evaluation was performed. The patients were brought intothe procedure room, and a VAS pain score was taken (0 mm—no pain, 100mm—extreme pain). Once the patient had marked his or her pain on thecard, he/she was prepped for knee cannulation. Once the cannula wasplaced, the patient received by intra-articular infiltration, 3 mg/kg(maximum dose of 200 mg) of 2% lignocaine into the knee scheduled to bereplaced. This administration of local anesthetic was followed in 10minutes by an intra-articular infiltration of placebo (vehicle) or 10μg, 100 μg, or 300 μg of purified capsaicin diluted with vehicle to atotal volume of 5 mL.

VAS pain scores as well as verbal reports were taken immediatelyfollowing administration, as welt as prior to knee replacement surgery.No subjects discontinued from the study due to adverse events.

Immediately following instillation of capsaicin, some patients (0 of 4receiving placebo, 0 of 4 receiving 10 μg capsaicin, 1 of 4 receiving100 μg capsaicin, and 4 of 4 receiving 300 μg capsaicin) reportedtransient burning pain representative of capsaicin injection (onsetwithin a few seconds to minutes and lasting less than one hour). Painwas mild but for some patients, the investigator chose to place icepacks on the treated knee until the pain resolved. In particular, thesubject in the 100 μg dose group and 2 of the subjects in the 300 μgdose group had burning post-administration (hyper) algesic pain alone;two subjects in the 300 μg dose group had burning pain in conjunctionwith other types of post-administration (hyper) algesic pain (1 subjecthad burning and stinging pain and the second subject had burning andtoothache-like pain). All of the episodes of post-administration (hyper)algesia began immediately (within 5 minutes) after administration. Allof these painful episodes were brief: the duration of this pain was 9minutes for the subject in the 100 μg dose group, and 17, 25, 25, and 42minutes for the subjects in the 300 μg dose group. The 4 subjects in the300 μg dose group and I subject in the 100 μg dose group requiredintervention for their post-injection (hyper) algesia. For all but 1 ofthese 5 subjects, the only intervention was ice packs. One subject inthe 300 μg dose group was treated with paracetamol; no subjects weretreated with intravenous morphine or granisetron for post-administration(hyper) algesia. Most of the concomitant medications used in the studywere medications taken prior to the study that continued to be takenduring the study. The only concomitant non-drug treatments during thestudy were the ice packs used in the 5 subjects with post-adminitration(hyper) algesia.

On the Post-Treatment Day, study evaluation was performed followed bythe scheduled knee replacement, with intra-operative bone and softtissue biopsies performed for subsequent examination. For overallefficacy analysis, we chose to exclude the patients who had surgery twodays following administration since analgesia from-remaining lignocaineor residual pain from the actual procedure (large volume infiltration)and lysing c-fiber endings could not be excluded (In normal volunteers,a mild “aching” pain is sometimes observed for up to two days followingcapsaicin administration). This therefore left the 3 placebo and 9active patients from the 4 day, 7 day, and 14 day cohorts. Examinationof the VAS scores prior to drug/placebo administration and the day ofsurgery (prior to surgery) showed that pain scores were not reduced inthe placebo group (VAS decreased by only 7±30%), but was reduced in thecapsaicin group (VAS reduced by 62±14%). The changes in VAS score arereported graphically as shown in FIG. 1. The plasma concentration overtime of the three dosage ranges of capsaicin are shown in FIG. 2.

Ten-mL blood samples for subsequent assay of plasma ultra-purifiedcapsaicin concentrations were collected prior to study medicationadministration, at 30 minutes, 1, 2, and 4 hours after study medicationinjection, and immediately prior to the first administration ofpre-operative medications on the Post Treatment Day. The pharmacokineticparameters of Cmax, Tmax, AUC(0−t_(last)) and t½ were evaluated.

In the 10 μg dose group, purified capsaicin plasma concentrations weremeasurable at only 0, 1, or 2 time points; therefore, no pharmacokineticparameters could be estimated for any subject in this dose group. Forthe 3 subjects in each of the 100 μg, and 300 μg dose groups for whichpharmacokinetic parameters could be estimated, the magnitude of the Cmaxand AUC(0−t_(last)) values was similar in the 2 dose groups. Tmax valueswere 0.5 hr in all subjects for which they could be estimated. Terminalexponential half-lives were similarly brief in all subjects in both the100 μg and 300 μg dose groups.

The AUC (0−t_(last)) values for the subjects in the 100 μg dose group(366.10, 75.19, and 511.21 pg*hr/mL) were similar in magnitude to thevalues for the 300 μg dose group (449.01, 220.42, and 498.83 pg*hr/mL).Similarly, the C_(max) values in the 100 μg dose group (292.06, 79.94,and 538.32 pg/mL) were similar in magnitude to the values in the 300 μgdose group (207.62, 251.42, and 499.88 pg/mL). T_(max) was 0.5 hours inall 6 subjects. The terminal exponential half lives were brief in allsubjects, with values of 0.1498, 1.1488, and 0.1014 hr in the 100 μgdose group and values of 0.3268, 0.2298, and 0.1663 in the 300 μg dosegroup.

The pharmacokinetic conclusions are necessarily limited, because thenumber of timepoints at which plasma concentrations of purifiedcapsaicin was measurable was so limited in these study subjects.However, there was some evidence for a pharmacokinetic dose responseover the 10 μg to 300 μg dose range in that the purified capsaicinplasma concentrations in the 10 μg dose group were clearly lower than ineither the 100 μg or the 300 μg dose groups. However, there was littleevidence for a pharmacokinetic dose response over the 100-300 μg doserange.

Purified capsaicin was well tolerated at all dose levels. There was lowleakage of study drug from the joint space and gross and microscopicpathology was normal. There were no treatment related signs of eryhema,edema, or hemorrhage at the site of injection, and no treatment relatedeffects on soft tissue, cartilage, or bone upon histopathologicalexamination. No treatment related systemic side effects were seen, andthere were no treatment related effects on laboratory safety parametersor vital signs. There was no discemable effect on proprioception at theinjected knee in any dose group at any time point.

There was a clear dose response for the incidence of post injectionhyperalgesia. This symptom occurred in 4 subjects in the 300 μg dosegroup, 1 subject in the 100 μg dose group, and no subjects in the 10 μgdose group or placebo. In all but one case, the hyperalgesia wasdescribed as a burning sensation, which developed within five minutes ofinjection and lasted on average less than thirty minutes. In all caseswhere intervention was required, the hyperalgesia was easily andeffectively controlled by the application of ice packs to the knee.

Subjects were asked to rank their level of pain on a visual analoguescale (VAS), anchored by “no pain” on the left and “extreme pain” on theright, prior to receiving the intra-articular dose of purified capsaicinand local anesthetic and then again just prior to administration ofpreoperative medications on the day of knee replacement surgery. Noclear treatment related indication of efficacy was seen at any of thedose levels (10 μg, 100 μg, and 300 μg) of purified capsaicin.

Since intra-articular infiltration of local anesthetic followed byintra-articular infiltration of capsaicin was generally well-tolerated,and the median decreases from baseline to the pre-operative time pointin the VAS for pain at the target knee in all 3 capsaicin dose groupswere all substantially greater that the median change from baseline inthe placebo group, the risk to benefit ratio of this treatment strategyappears favorable. Further studies of this treatment in larger numbersof subjects with osteoarthritis appear warranted.

EXAMPLE II Osteoarthritis of the Knee Efficacy Study

The following clinical study evaluates the efficacy of purifiedcapsaicin administered by intra-articular infiltration together with alocal anesthetic injected by intra-articular infiltration in subjectswith osteoarthritis of the knee.

The primary objective of the study is to evaluate the efficacy ofintra-articular capsaicin, when co-administered with intra-articularlocal anesthetic, compared to placebo, in subjects with end-stageosteoarthritis of the knee, already scheduled to receive kneereplacements (21 and 42 days after injection of study medication).

Purified capsaicin is supplied in vials containing 5 mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug was stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle is used to dilute the drug to final concentrations ofpurified capsaicin, as follows: TABLE 2 Dose Level Concentration TotalVolume of Dose 1000 μg 200 μg/mL 5 mL

Each vial is used for one infiltration administration only andappropriately labeled. The supplier of the purified capsaicin isFormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vialsare supplied in bulk to the study center with each vial labeledaccording to the contents of the vial. The Pharmacist/Study Nurse, whoprepares the injection, maintaines the investigational product in alockable cabinet at the required temperature, 15-25° C. The study blindis maintained by the Pharmacist/Study Nurse.

Placebo vehicle for purified capsaicin is supplied in vials containing 5mL. Local anesthetic (Lignocaine 2%) is used for each subacromial bursainfiltration.

The study is a single center, randomized, double blind, placebocontrolled, dose ranging Phase 2 study of capsaicin (1000 μg)administered by intra-articular infiltration, when co-administered withintra-articular local anesthetic, in subjects with osteoarthritis of theknee who are scheduled to undergo total knee replacement from three tosix weeks post study drug administration, wherein the primary endpointis pain reduction at three weeks following study drug administration.

The study is designed to include 12 evaluation subjects (Patientssuffering a defined pain: >40 mm on VAS). Six (6) subjects will betreated with capsaicin 1000 μg and 6 subjects will be treated withplacebo vehicle. Patients are treated randomly and in double-blindfashion. Gross and microscopic pathology analysis are completed for eachtreatment group. Each subject has 3 study visits: a Screening Day (Day−7 to −1), the Treatment Day (Day 0), and a Post-Treatment Day(scheduled for Day +2, +4, +7, or +14). On the Treatment Day the subjectis randomized, pre-treatment evaluation is performed. The patient isbrought into the procedure room, and a VAS pain score is taken (0 mm—nopain, 100 mm—extreme pain). Once the patient marks his or her pain onthe card, he/she is prepped for knee cannulation. Once the cannula isplaced, the patient receives, by intra-articular infiltration, 3 mg/kg(maximum dose of 200 mg) of 2% lignocaine into the knee scheduled to bereplaced. This infiltration of local anesthetic is followed in 10minutes by an intra-articular infiltration of placebo (vehicle) or 1000μg of purified capsaicin diluted with vehicle to a total volume of 5 mL.

VAS pain scores as well as verbal reports are taken immediatelyfollowing administration, as well as prior to knee replacement surgery.On the Post-Treatment Day, a study evaluation is performed followed bythe scheduled knee replacement, with intra-operative bone and softtissue biopsies performed for subsequent examination. For overallefficacy analysis, patients having surgery two days followinginfiltration are excluded since analgesia from remaining lignocaine orresidual pain from the actual procedure (large volume injection) andlysing c-fiber endings is not capable of being excluded.

Changes in NRS (Numerical Rating Scale) pain scores were measured atthree weeks following administration. Final NRS score for placebo=7.30(p=0.05), whereas final NRS score for capsaicin=3.97 (P=0.03) (See FIG.3).

EXAMPLE III Bunionectomy Efficacy Study

The following study was carried out in order to evaluate the safety,tolerability, systemic pharmacokinetics, and efficacy of intra-operative(infiltration) capsaicin when co-administered with a local anesthetic inpatients scheduled to undergo transpositional osteotomy (bunionectomy).

The primary objective of the study was to evaluate the safety andtolerability of capsaicin, when co-administered by intra-articularinfiltration with a local anesthetic, compared to placebo, in subjectswith hallux valgus deformity, already scheduled to undergotranspositional osteotomy (bunionectomy). The secondary objective of thestudy was to evaluate the safety, tolerability and systemicpharmacokinetics of purified capsaicin following intra-operativeadministration. The primary efficacy endpoint was the proportion ofsubjects in each treatment group requiring opioid analgesia in the first24 hours post-operatively. The proportions were compared amongsttreatment groups using the Cochran-Haenszel test. Secondary efficacy endpoints included: i) proportion of subjects in each treatment grouprequiring opioid analgesia in the first 36 hour period post-operatively(Similarly, the proportions were compared amongst treatment groups usingthe Cochran-Haenszel test) ; ii) proportion of subjects in eachtreatment group requiring opioid analgesia in the 10 day periodpost-operatively (Similarly, the proportions were compared amongsttreatment groups using the Cochran-Haenszel test) ; iii) time to firstusage of opioid analgesia in each treatment group (a survival analysisapproach will be used: the product-limit (Kaplan-Meier) method will beapplied to time to first usage of opioid analgesia. The median time tofirst usage of opioid analgesia will be estimated in both treatmentgroups. Pairwise comparisons will be performed to test for equality ofthe survival curves between the 2 treatment groups using both thelog-rank and the Wilcoxon test); iv) total usage of analgesia in eachtreatment group (the total usage of analgesia will be compared by ananalysis of variance with treatment and center as independent variables.A pairwise comparison will be performed between the treatment groups);and v) VAS assessment of pain at the site of operation in each treatmentgroup (The VAS score at each time point will be compared by an analysisof variance with treatment and center as independent variables. Apairwise comparison will be performed between the treatment groups).Safety endpoints included: i) laboratory safety parameters; ii) adverseevents; and iii) purified capsaicin blood levels. The efficacy analysiswas performed on the data obtained ten days postoperatively. The safetyanalysis was performed based on the safety data for the entire study,including the 6 week and 12 week follow-up periods. The blind was brokenat the time the efficacy analysis was performed. However, the individualtreatment assignment was available to the statistical analysis grouponly. All other personnel involved in the study, including theInvestigator, study monitor and proprietary staff, remained blindeduntil the entire study was completed.

Purified capsaicin was supplied in vials containing 5 mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug was stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle was used to dilute the drug to final concentrationsof purified capsaicin, as follows: TABLE 3 Dose Level ConcentrationTotal Volume of Dose 1000 μg 250 μg/mL 4 mL

Each vial was used for one infiltration administration only andappropriately labeled. The supplier of the purified capsaicin wasFormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vialswere supplied in bulk to the study center with each vial labeledaccording to the contents of the vial. The Pharmacist/Study Nurse, whoprepared the injection, maintained the investigational product in alockable cabinet at the required temperature, 15-25° C. The study blindwas maintained by the Pharmacist/Study Nurse.

Placebo vehicle for purified capsaicin was supplied in vials containing5 mL. Local anesthetic (Lignocaine 2%) was used for each infiltration.

The study was a single center, randomized, double blind, placebocontrolled, Phase II study of the safety and efficacy of intra-operativecapsaicin, when co-administered with local anaesthetic, in subjectsundergoing transpositional first metatarsal osteotomy and fixation forthe correction of hallux valgus deformity. The dose of capsaicin used inthe trial was 1000 μg.

The study was designed to include 40 evaluation subjects. Twenty (20)randomized to the capsaicin treatment group and twenty (20) to theplacebo control group. Each subject had six (6) study visits: aScreening Day (Day −28 to −1), an Operation Day (Day 0), and four (4)Follow-up visits (scheduled for Days 3, 10 and weeks 6 and 12).

On Operation Day (Day 0) the following was performed: a) Pre-operation:Prior to the initiation of an ankle block, inclusion/exclusion criteriaassessment was performed. Eligible subjects were randomized,pre-treatment evaluation was performed, which included laboratory safetyassessments, measurement of vital signs, VAS assessment of pain at thetarget Hallux valgus, blood sample measurement fo purified capsaicinconcentration, and review of concomitant medications; b) Operation: Anankle block [lidocaine 0.5% (up to a total of 20 ml)] was initiated bythe investigator to provide surgical anesthesia, and then atranspositional osteotomy of the first metatarsal ± an Akin osteotomy ofthe proximal phalanx in accordance with normal practices and procedureswas performed. Immediately prior to wound closure, the Investigatorslowly dripped the study medication (4 mL) from a syringe into thewound, ensuring even tissue exposure. The wound was then closedaccording to normal practices and procedures.

Post-Operation:

In the 24 hours following administration of study medication, vitalsigns (supine pulse rate and blood pressure) were recorded at 1, 2, 4and 24 hours post administration. VAS assessment of pain at theoperation site was performed at 1, 4, 8, 12 and 24 hours postadministration. In those instances where VAS measurements coincide withblood sampling procedures, the VAS assessment was performed first. Bloodsamples for measurement of capsaicin concentration were obtained at 1,2, and 4 hours post administration. The quantity of each blood samplewas 10 mL. Laboratory safety assessments, e.g., haematology,biochemistry, urinalysis were performed at 24 hours post administration.Adverse events were spontaneously reported by the subject and recorded.Rescue analgesia medication was provided to the subject if required(initially diclofenac 50 mg, repeated at 8 hourly intervals ifnecessary). When diclofenac was judged by the Investigator toprovide-inadequate pain relief then the subject was provided withalfentanil, 1 mg, repeated at 6 hourly intervals when necessary. Upondischarge from the hospital, alfentanil was substituted with co-codamol30/500 (codeine phosphate 30 mg+paracetamol 500 mg), repeated at 4hourly intervals when necessary. Any usage of rescue medication orconcomitant medication was recorded in the subject's CRF. At 24 hourspost administration of study medication, the subject was discharged fromthe clinic.

Follow Up:

Follow-up (days 1-10): Upon discharge from the clinic, the subject wasprovided with a diary card for Days 1-10, and asked to record: VASassessment of pain at the operation site, performed each morning; timeand amount of any rescue medication taken by the subject (at any time);usage of concomitant medications (at any time); adverse eventsexperienced by the subject (at any time). Each subject was also be askedto return to the clinic on Day 3 and on Day 10 post-operation. At theseclinic visits the Investigator examined the subject's diary card andresolved any unclear or inconsistent entries. Data from the diary cardwas transcribed to the subject's CRF. The site of the operation wasinspected by the Investigator to confirm that normal wound healing tookplace.

Follow Up (Week 6): The subject was asked to return to the clinic at 6weeks post operation. The site of the operation was inspected by theInvestigator to confirm that normal wound healing is took place. Thesubject was questioned about any adverse events he/she experienced sincethe last clinic visit, and any usage of concomitant medication.

Follow Up (Week 12): The subject was asked to return to the clinic at 12weeks post operation. The site of the operation was inspected by theInvestigator to confirm that normal wound healing is took place. Thesubject was questioned about any adverse events he/she may experiencedsince the last clinic visit, and any usage of concomitant medication.The Investigator discharge the subject from the study.

The results of the bunionectomy study proved that capsaicin administeredat a dose of 1000 μg into the wound prior to wound closure reduced bothpain score as well as the use of rescue as shown in FIGS. 3 and 4.Reduction in rescue was almost always associated with maintenance of VASscore, i.e., the new drug simply substitutes for the old drug (See;Table 4 below): TABLE 4 Time Placebo purified capsaicin  1 hr  3.3 +/−2.3 11.1 +/− 7.3   4 hr  3.1 +/− 2.2 10.7 +/− 3.6   8 hr 19.7 +/− 4.95.5 +/− 2.3 12 hr 28.1 +/− 9.0 8.2 +/− 3.8 24 hr 11.7 +/− 4.6 1.9 +/−1.0 48 hr 19.3 +/− 8.9 5.9 +/− 2.5 72 hr 22.9 +/− 9.9 10.6 +/− 3.5 mean +/− SEM n = 10 placebo, n = 11 purified capsaicinP < 0.05 at each time point

Administration of 1000 μg of capsaicin prior to wound closure decreasedopioid rescue. Only 45% of the study subjects randomized to receivecapsaicin required rescue (one subject required rescue at 1 hr, a secondsubject required rescues at 4 hr, a third subject required rescue at 5hr, a fourth subject required rescue at 8 hr, and a fifth subjectrequired rescue at 12 hr; 6 subjects did not rescue in 72 hours (n=11)),whereas 80% of the study subjects randomized to receive placebo requiredrescue (one subject required rescue at 1 hr, a second subject requiredrescue at 2 hr, a third subject required rescue at 6 hr, a fourthsubject required rescue at 8 hr, a fifth subject required rescue at 12hr, a sixth subject required rescue at 14 hr, a seventh and eighthsubject required rescue at 16 hr, and 2 subjects did not require rescuein 72 hours (n=10) P<0.05).

EXAMPLE IV Epicondylitis Safety and Efficacy Study

The primary objective of the study is to evaluate the safety andefficacy of and to determine the duration of effect of a single dose ofcapsaicin in subjects with recent onset of acute epicondylitis. Theprimary efficacy endpoint is the assessment of pain at Day 28 (3 days)as defined by Subject evaluation of pain on movement, measured by theVAS scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days)post-treatment. The secondary efficacy endpoints are: i) subjectassessment of symptoms on movement, measured by the 5-point scale at 1hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; ii)Investigator assessment of tenderness, measured by the 5-point scale at1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment;iii) Investigator global evaluation of improvement, measured by the6-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days)post-treatment; and iv) subject global evaluation of improvement,measured by the 6-point scale at 1 hour, 3 hours, 7 days (2-days) and 28days (3 days) post-treatment.

Purified capsaicin is supplied in vials containing 5mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug is stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle is used to dilute the drug to final concentrations ofpurified capsaicin, as follows: TABLE 5 Dose Concentration Total Volumeof Dose 600 μg 300 μg/ml 2 ml

Each vial is used for one subcutaneous injection only and appropriatelylabeled. The supplier of the purified capsaicin is FormaTech, Inc., 200Bullfinch Drive, Andover, Mass. 01810. The vials are supplied in bulk tothe study center with each vial labeled according to the contents of thevial. The Pharmacist/Study Nurse, who prepares the injection, maintainsthe investigational product in a lockable cabinet at the requiredtemperature, 15-25“C. The study blind is maintained by thePharmacist/Study Nurse.

Placebo vehicle for purified capsaicin is supplied in vials containing 5mL. Local anesthetic (Lignocaine 2%) is used for each subcutaneousinjection.

Patient evaluation of pain on movement, measured by a Visual AnalogScale (VAS) is analyzed using an analysis of covariance model covaringon the baseline VAS score. Investigator global evaluation of improvementand Patient global evaluation of improvement is analyzed using a CochranMantel-Haenszel test.

Each subject is asked to provide a Numerical Pain Scale value for painimmediately upon injection, pain after 1 hour, and pain after 3 hours.Vital signs and physical examination are collected at baseline (Visit 1)and Visit 4. Routine clinical hematology, clinical chemistry andurinalysis measurements will be made prior to dosing (Visit 1) and againat Day 28 (3 days). Safety and tolerability of purified capsaicin isassessed by the collection, review and analysis of adverse eventsreported during the course of the study.

This is a Phase II, multicenter, randomized, double-blind,placebo-controlled, fixed dose design study to assess the efficacy andsafety of a single administration, by subcutaneous injection of 600 μgof capsaicin or placebo in the treatment of acute epicondylitis.

Study treatment is administered to 40 subjects (20 randomized to receive600 μg of capsaicin and 20 randomized to receive placebo).

Each study subject has four (4) study visits: Baseline visit (day −7±4days); Visit 2 (Day 0); and Follow-up visits at Day 7 (2 days) and atDay 28 (3 days) after the administration of study treatment.

Visit 1 (day −7±4 days) baseline assessments are initiated, whichinclude medical history, physical exam, vital signs, review ofconcomitant medication use, elbow pain history, clinical evaluation ofthe elbow as follows: i) subject's assessment of symptoms on movement(0=none; 1=mild; 2=moderate; 3=severe; 4=very severe); ii) subject'sevaluation of pain on movement (100 mm VAS, where 0=no pain and100=worst imaginable); and iii) investigator's assessment of tenderness(0=no tenderness; 1=mild tenderness; 2=moderate tenderness; 3=severetenderness; 4=very severe tenderness). A review of inclusion/exclusioncriteria as well as laboratory assessments are conducted.

At Visit 2 (Day 0), subjects are evaluated for eligibility. A review ofconcomitant medication use is conducted with changes from Visit 1recorded in subject's CRF. Clinical evaluation of elbow - pre-dose: i)subject assessment of symptoms on movement (5-point scale); ii)subject's evaluation of pain on movement (VAS); and Investigatorassessment of tenderness (5-point scale). Eligible study subjects arerandomized to receive either capsaicin 600 μg or placebo. Study drug isadministered according to the following procedure: the study subject ispositioned in the sitting position with their elbow resting flexed on afirm surface. Aseptic technique is observed. The skin around the site ofadministration is cleaned. Then up to 1.0 mL of 2% lidocaine is injectedby deep subcutaneous injection into muscle and tissue 1 cm distal to thelateral/medial epicondyle and aiming towards the tender spot, 10 minutesprior to injection with study drug. Study drug is then injected and firmpressure is applied to the injection site.

Once the study drug is administered, the study subject is asked toprovide an NPS value for pain immediately upon injection, and 1 and 3hours after injection. Clinical evaluation of the elbow is performed at1 and 3 hours after injection utilizing the following evaluationparameters: i) subject's evaluation of pain on movement (VAS); subjectassessment of symptoms on movement (5-point scale); iii) Investigatorassessment of tenderness (5-point scale); iv) Investigator's GlobalEvaluation of Improvement (−1=worse; 0=no change; 1=slight improvement;2=moderate improvement; 3=marked improvement; and 4=no symptoms); and v)subject's Global Evaluation of Improvement (−1=worse; 0=no change;1=slight improvement; 2=moderate improvement; 3=marked improvement; 4=nosymptoms). A review of adverse events is conducted.

Some subjects receiving capsaicin may experience a short-lived painfulburning sensation post-injection. This is usually adequately controlledby the application of ice packs until the symptoms have resolved, oruntil a maximum of 20 minutes have passes. (which ever is shorter).However, when additional analgesic management is required, a bolusinjection of morphine is administered, which is preceded by a singlebolus injection of granisetron (3 mg). Additionally, rescue medicationin the form of paracetamol 500 mg tablets, will be provided to allsubjects at Visit 2 (Day 0). Subjects will be instructed to take 2paracetamol tablets (1 gm) every 4-6 hours up to a maximum of 4 g/day ifbreak through pain occurs.

On Visit 3 (day 7±2 days) the study subject is evaluated as follows:First, use of concomitant medications are evaluated. Changes from Visit2 are recorded on the study subject's CRF. A clinical evaluation of theelbow is performed utilizing the following evaluation parameters: i)subject's evaluation of pain on movement (VAS); ii) subject's assessmentof symptoms on movement (5-point scale); iii) investigator's assessmentof tenderness (5-point scale); iv) investigator's Global Evaluation ofImprovement (6-point scale); and v) subject's Global Evaluation ofImprovement (6-point scale). A review of adverse events is conducted.

On Visit 4 (day28±3 days) the study subject is evaluated (physical exam,vital signs, laboratory assessments). Use of concomitant medication isreviewed with any changes from Visit 3 recorded in the subject's CRF.The following clinical evaluation of the elbow is conducted: i)subject's evaluation of pain on movement (VAS); ii) subject's assessmentof symptoms on movement (5-point scale); iii) investigator's assessmentof tenderness (5-point scale); iv) investigator's Global Evaluation ofImprovement (6-point scale); and v) subject's Global Evaluation ofImprovement (6-point scale). A review of adverse events is conducted andthe patient is subsequently discharged from the study.

EXAMPLE V Shoulder Safety and Efficacy Study

The primary objective of the study is to evaluate the safety andefficacy of and to determine the duration of effect of a single dose ofcapsaicin in subjects with recent onset of painful shoulder. The primaryefficacy endpoint is the assessment of pain and function at Day 28 (3days) as defined by: i) subject evaluation of pain and disability indexon movement, measured by the SPADI scale at 28 days (3 days)post-treatment. The secondary efficacy endpoints are: Subject assessmentof SPADI score at 1 hours, 3 hours and 7 days (2 days); ii) subjectassessment of symptoms on movement, measured by the 5-point scale at 1hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; iii)Investigator assessment of tenderness, measured by the 5-point scale at1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment;iv) Investigator assessment of restricted movement, measured by degreeof active/passive abduction, presence of painful arc, active/passiveflexion and % of internal/external rotation with resistance at 1 hour, 3hours, 7 days (2 days) and 28 days (3 days) post-treatment; v)Investigator global evaluation of improvement, measured by the 6-pointscale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days)post-treatment; subject global evaluation of improvement, measured bythe 6-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3days) post-treatment.

Each subject is asked to provide a Numerical Pain Score value for painimmediately upon injection, pain after 1 hour, and pain after 3 hours.Vital signs and physical examination are collected at baseline (Visit 1)and Visit 4. Routine clinical hematology, clinical chemistry andurinalysis measurements are made prior to dosing (Visit 1) and again atDay 28 (3 days). Safety and tolerability of purified capsaicin is alsobe assessed by the collection, review and analysis of adverse eventsreported during the course of the study.

Purified capsaicin is supplied in vials containing 5 mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug is stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle is used to dilute the drug to final concentrations ofpurified capsaicin, as follows: TABLE 6 Dose Concentration Total Volumeof Dose 600 μg 300 μg/ml 2 ml

Each vial is used for one subcutaneous injection only and appropriatelylabeled. The supplier of the purified capsaicin is FormaTech, Inc., 200Bullfinch Drive, Andover, Mass. 01810. The vials are supplied in bulk tothe study center with each vial labeled according to the contents of thevial. The Pharmacist/Study Nurse, who prepares the injection, maintainsthe investigational product in a lockable cabinet at the requiredtemperature, 15-25° C. The study blind is maintained by thePharmacist/Study Nurse.

Placebo vehicle for purified capsaicin is supplied in vials containing 5mL. Local anesthetic (Lignocaine 2%) is used for each subcutaneousinjection.

This is a Phase II, multicenter, randomized, double-blind,placebo-controlled, fixed dose design study to assess the efficacy andsafety of a single administration, by subcutaneous injection of 600 μgof capsaicin or placebo in the treatment of painful shoulder.

Study treatment is administered to 54 subjects (27 randomized to receive600 μg of capsaicin and 27 randomized to receive placebo).

Each study subject has four (4) study visits: Baseline visit (day −7±4days); Visit 2 (Day 0); and Follow-up visits at Day 7 (2 days) and atDay 28 (3 days) after the administration of study treatment.

Visit 1 (day −7±4 days) baseline assessments are initiated, whichinclude medical history, physical exam, vital signs, review ofconcomitant medication use, shoulder pain history, clinical evaluationof the shoulder as follows: i) Shoulder Pain and Disability Index; ii)subject's assessment of symptoms on movement (5-point scale); iii)investigator's assessment of tenderness (5-point scale); and iv)investigator's measurement of restricted movement. A review ofinclusion/exclusion criteria as well as laboratory assessments are alsoconducted.

At Visit 2 (Day 0), subjects are evaluated for eligibility. A review ofconcomitant medication use is conducted with changes from Visit 1recorded in subject's CRF. A clinical evaluation of shoulder- pre-doseis performed with using the following: i) Shoulder Pain and DisabilityIndex (SPADI); ii) subject assessment of symptoms on movement (5-pointscale); iii) Investigator assessment of tenderness (5-point scale); iv)Investigator's Measurement of Restricted Movement.

Eligible study subjects are randomized to receive either capsaicin 600μg or placebo. Study drug is administered according to the followingprocedure: the study subject is positioned in the sitting position.Aseptic technique is observed. The skin around the site ofadministration is cleaned. Then up to 1.0 mL of 2% lidocaine isadministered by subacromial bursa injection, 10 minutes prior toinjection of the study drug. Study drug is injected into the subacromialbursa with a 22-gauge 1.5 inch needle inserted into the space betweenthe acromium and the humerus on the lateral aspect of the shoulder. Theneedle is withdrawn cleanly and firm pressured is applied to theinjection site.

Once the study drug is administered, the study subject will be asked toprovide an NPS value for pain immediately upon injection, and 1 and 3hours after injection.

Clinical evaluation of the shoulder is performed at 1 and 3 hours afterinjection utilizing the following evaluation parameters: i) ShoulderPain and Disability Index; ii) subject's assessment of symptoms onmovement (5-point scale); iii) investigator's assessment of tenderness(5-point scale); iv) investigator's measurement of restricted movement;v) investigator's Global Evaluation of Improvement (−1=worse; 0=nochange; 1=slight improvement; 2=moderate improvement; 3=markedimprovement; 4=no symptoms); and vi) subject's Global Evaluation ofImprovement (6-point scale). A review of adverse events is conducted.

Some subjects receiving capsaicin may experience a short-lived painfulburning sensation post-injection. This is usually adequately controlledby the application of ice packs until the symptoms have resolved, oruntil a maximum of 20 minutes have passes. (which ever is shorter).However, when additional analgesic management be required, a bolusinjection of morphine is administered, which is preceded by a singlebolus injection of granisetron (3 mg).

On Visit 3 (day 7±2 days) the study subject is evaluated as follows:First, use of concomitant medications are evaluated. Changes from Visit2 are recorded on the study subject's CRF. A clinical evaluation of theshoulder is performed utilizing the following evaluation parameters: i)Shoulder Pain and Disability Index; ii) subject's assessment of symptomson movement (5-point scale); iii) investigator's assessment oftenderness (5-point scale); iv) investigator's measurement of restrictedmovement; v) investigator's Global Evaluation of Improvement (6-pointscale); and vi) subject's Global Evaluation of Improvement (6-pointscale). A review of adverse events is conducted.

On Visit 4 (day 28±3 days) the study subject is evaluated (physicalexam, vital signs, laboratory assessments). Use of concomitantmedication is reviewed with any changes from Visit 3 recorded in thesubject's CRF. The following clinical evaluation of the shoulder isconducted: i) Shoulder Pain and Disability Index; ii) subject'sassessment of symptoms on movement (5-point scale); iii) investigator'sassessment of tenderness (5-point scale); iv) investigator's measurementof restricted movement; v) investigator's Global Evaluation ofImprovement (6-point scale); and vi) subject's Global Evaluation ofImprovement (6-point scale). A review of adverse events is conducted andthe patient is subsequently discharged from the study.

EXAMPLE VI Median Sternotomy Study

The primary objective of the study is to determine the amount of opioidconsumption and postoperative pain scores following median sternotomyfor patients receiving purified capsaicin by infiltration and/orinjection. Eligible subjects are patients undergoing cardiac, pulmonary,or mediastinal surgery for any indication between the ages of 20-70years. The operation is performed under general anesthesia and areclosely observed in a post-anesthesia care unit as per the practice ofthe institution. The study drug will be administered to the sternaledges, muscles (e.g., muscle edges), bone (e.g., bone edges), andtissues. All patients will receive standard of care opioid on demand fortreatment of pain when transferred to the ward. The dose of capsaicin isadministered to the sternal edges, the muscle.

Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutesbeginning when the patient first is placed in a bedside chair (orambulated) for 24 hours and then every 4 hours while awake untildischarge from the hospital. Patient diaries will be used followingdischarge for a two-week period.

The primary study endpoint is the time to first request of postoperativeopioid. The amount of opioid rescue used is recorded every 24 hours forthe first 2 weeks, patients will complete an opioid-related symptomdistress (SDS) questionnaire.

EXAMPLE VII Chronic Post-Herniorrhapy Study

This study will evaluate the efficacy of purified capsacin administeredby injection for the treatment of chronic post-herniorhappy pain insubjects who are >6 months after open inguinal herniorrhaphy withchronic pain from the surgical area influencing some type of socialactivities (work, leisure or sports activities, etc.). Study subjectswill receive a dose of purified capsaicin in proximity to the surgicalsite. Pain during rest and well-defined function in relation to factors,which may provoke pain (key end-points) are evaluated. In addition, QSTassessment of the surgical area before and after therapy is conducted.

EXAMPLE VIII Laparoscopic Choloecystectomy Study

The primary objective of this study is to evaluate the amount of opioidconsumption and postoperative pain scores following laparoscopiccholecystectomy in patients administered purified capsaicin byinfiltration and/or injection. Study subjects will receive a dose ofpurified capsaicin in proximity to the surgical site.

This study includes 40 patients (20 randomized to receive capsaicinstudy drug and 20 randomized to receive placebo study drug) between theages of 20-60 years old with symptomatic gallstones. The operation isperformed under general anesthesia and the subject is closely observedin a post-anesthesia care unit for up to 24 hours and remains in thehospital (typically for 1 to 5 days). All patients receive standard ofcare opioid on demand for treatment of pain before discharge, and opioid(to be determined) post discharge. Pain is assessed utilizing VAS 100 mmscale—baseline, every 30 minutes till the 2nd postoperative hour thenevery 4 hours the following 12 hours, an at 24 hours and at days 2, 3,4, 5, 6 and 7. Patient diaries are used following discharge. Studysubject will receive a, dose of purified capsaicin 1000-3000 μg dividedover the 4 part wounds-infiltrated along the cut muscle edges.

The primary study endpoint is the time to first request of postoperativeanalgesia The amount of opioid rescue is every 24 hours for first 3days, patients complete an opioid-related symptom distress (SDS)questionnaire.

EXAMPLE IX Morton's Neuroma Study

The primary objective of the study is to determine the short andintermediate term benefit of purified capsaicin administration byinjection in subjects with Morton's Neuroma.

Subjects with pain in the ball of the foot, often radiating into the 3rdand 4th toes, with localized intermetatarsal tenderness diagnostic ofMorton's Neuroma, Anteroposterior and lateral radiographs of theinvolved foot that reveal evidence of no other bony or soft tissuedisorders, patients who have previously responded to local anesthetics,steroid injections, or have amputation neuroma are eligible for thestudy. Study subjects will receive a dose of purified capsaicin at thesite, and baseline pain is assessed utilizing a patient diary based on a100 mm VAS scale. For inclusion in the trial, mean pain score for the 5days prior to randomization must be greater than 40 mm.

The endpoint of the study is pain measured on a 100 mm VAS, as assessedin the patient diary. Pain scores are averaged on a weekly basis for the8 weeks following injection. Patients will continue to be followedlong-term (minimum 4 months).

In the preceding specification, the invention has been described withreference to specific exemplary embodiments. Those skilled in the artwill recognize, or be able to ascertain using no more than routineexperimentation, many equivalents to the specific embodiments to themethods described herein. Such equivalents are intended to beencompassed by the following claims.

EXAMPLE X Knee Replacement Study

The primary objective of the study is to evaluate the amount of opioidconsumption and postoperative pain scores following knee replacementsurgery for patients receiving administration of purified capsaicin byinfiltration.

This study includes 80 patients (20 patients are randomized to receiveplacebo, 20 randomized to receive capsaicin 300 μg, 20 randomized toreceive capsaicin 1000 μg, and 20 randomized to receive capsaicin 2000μg). Eligible subjects are patients who undergoing knee replacementsurgery between the ages of 20-70 years old.

The knee replacement operation is performed under general anesthesia andis closely observed in a post-anesthesia care unit as per the practiceof the institution. All patients receive standard of care opioid ondemand for treatment of pain once transferred to the ward. The volume ofcapsaicin administered into the wound opening during closure ranges fromabout 5 ml to about 10 ml.

Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutesbeginning when the patient first is placed on mechanicalflexion/extension for 24 hours and then every 4 hours while awake untildischarge from the hospital. Patient diaries are used followingdischarge for a two-week period.

EXAMPLE XI Mastectomy Study

Mastectomy results in significant pain and requires substantial doses ofopioids postoperatively. Analgesic techniques that provide good paincontrol while minimizing opioid side effects are thus highly desirable.The primary objective of the study determines the amount of opioidconsumption and postoperative pain scores following mastectomy forpatients receiving capsaicin.

The study includes 80 patients (20 patients are randomized to receiveplacebo, 20 randomized to receive capsaicin 300 μg, 20 randomized toreceive capsaicin 1000 μg, and 20 randomized to receive capsaicin 2000μg). Eligible patients include patients undergoing mastectomy betweenthe ages of 20-70 years old. The operation is performed under generalanesthesia and is closely observed in a post-anesthesia care unit as perthe practice of the institution. All patients receive standard of careopioid on demand for treatment of pain once transferred to the ward.

The dose of study drug is administered by infiltration in a volume fromabout 5 ml to about 10 ml within the wound cavity during closure.

Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutesbeginning when the patient first is placed on mechanicalflexion/extension for 24 hours and then every 4 hours while awake untildischarge from the hospital. Patient diaries are used followingdischarge for a two-week period.

The primary endpoint is time to first request of postoperative opioid.Opioid rescue occurs every 24 hours for the first 2 weeks, patientscomplete an opioid-related symptom distress (SDS) questionnaire.

Conclusion

The invention has been described in an illustrative manner, and it is tobe understood that the particular embodiments of the capsaicinoidformulations and methods of treatment described herein are intended tobe descriptive rather than limiting. Many modifications and variationsof the methodologies and formulations disclosed herein are possible inlight of the above teachings, and such obvious modifications are deemedto be encompassed within the scope of the appended claims.

1. A method for attenuating pain at a site in a human or animal in needthereof, comprising: administering at a discrete painful site in a humanor animal in need thereof a single injectable or implantable dose of acapsaicinoid in an amount effective to denervate said discrete sitewithout eliciting an effect outside the discrete location and toattenuate pain emanating from said site, said effective dose being fromabout 1 μg to about 5000 μg of capsaicin or a therapeutically equivalentdose of a capsaicinoid other than capsaicin.
 2. The method of claim 1,wherein said dose of capsaicin is from about 10 to about 3000 μg.
 3. Themethod of claim 1, wherein said dose of capsaicin is from about 300 toabout 1500 μg.
 4. The method of claim 1, wherein said dose of capsaicinis from about 400 to about 1200 μg.
 5. The method of claim 1, whereinsaid dose of capsaicinoid is administered in a pharmaceuticallyacceptable vehicle for injection or implantation.
 6. The method of claim4, wherein said pharmaceutically acceptable vehicle is an aqueousvehicle is selected from the group consisting of Sodium ChlorideInjection, Ringers Injection, Isotonic Dextrose Injection, Sterile WaterInjection, Dextrose, Lactated Ringers Injection and any combinations ormixtures thereof.
 7. The method of claim 5, wherein saidpharmaceutically acceptable vehicle comprises an agent selected form thegroup consisting of antimicrobial agents, isotonic agents, buffers,antioxidants, local anesthetics, suspending and dispersing agents,emulsifying agents, sequestering, chelating agents and any combinationsthereof.
 8. The method of claim 5, wherein said pharmaceuticallyacceptable vehicle comprises about 20% PEG 300, about 10 mM histidineand about 5% sucrose in water for injection.
 9. The method of claim 1,wherein said dose of capsaicinoid is injected or implanted into a siteselected from the group consisting of subcutaneous, intramuscular,itrathecal, epidural, intraperitoneal, caudal, intradermal, orintracutaneous, intercostal at a single nerve, intra-articular,intrasynovial, intraspinal, intra-arterial, at a laparoscopic surgicalsite, and a body space.
 10. The method of claim 7, wherein saidintra-articular administration comprises administration into a jointselected from the group consisting of knee, elbow, hip,sternoclavicular, temporomandibular, carpal, tarsal, wrist, ankle,intervertebral disk, ligamentum flavum and any other joint subject topain.
 11. The method of claim 1, wherein said dose of capsaicinoid isadministered in the form of injectable or implantable microparticlesselected from the group consisting of microcapsules and microspheres.12. The method of claim 1, further comprising administering a localanesthetic prior to or concurrently with said dose of capsaicinoid in anamount and location effective to attenuate an initial hyperalgesiceffect of said administered dose of capsaicinoid.
 13. The method ofclaim 12, wherein said local anesthetic is selected from the groupconsisting of dibucaine, bupivacaine, ropivacaine, etidocaine,tetracaine, procaine, chlorocaine, prilocaine, mepivacaine, lidocaine,xylocaine, 2-chloroprocaine, and acid addition salts or mixturesthereof.
 14. The method of claim 13, wherein said local anesthetic isadministered by direct injection into the site where said dose ofcapsaicinoid is administered.
 15. The method of claim 13, wherein saidlocal anesthetic is administered to said site as a regional nerve block.16. The method of claim 1, further comprising administering phenol priorto or concurrently with said dose of capsaicinoid in an amount andlocation effective to attenuate an initial hyperalgesic effect of saidadministered dose of capsaicinoid.
 17. The method of claim 1, whereinsaid administration of capsaicinoid at said discrete site providesattenuation of pain emanating from said site for at least about 48hours.
 18. The method of claim 1, wherein said dose comprises capsaicin.19. The method of claim 1, wherein said dose comprises a capsaicinoidother than capsaicin.
 20. The method of claim 19, wherein saidcapsaicinoid is selected from the group consisting of resiniferatoxin,N-vanillylnonanamides, N-vanillylsulfonamides, N-vanillylureas,N-vanillylcarbamates, N[(substituted phenyl)methyl]alkylamides,methylene substituted N[(substituted phenyl)methyl]alkanamides,N[(substituted phenyl) methyl]-cis-monosaturated alkenamides,N[(substituted phenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide,hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin,nordihydrocapsaicin anandamide, piperine, zingerone, warburganal,polygodial, aframodial, cinnamodial, cinnamosmolide, cinnamolide,isovelleral, scalaradial, ancistrodial, β-acaridial, merulidial,scutigeral, and any combinations thereof.
 21. The method of claim 20,wherein said capsaicinoid is resiniferatoxin.
 22. The method of claim18, wherein said capsaicin consists essentially of trans-capsaicin. 23.The method of claim 1, wherein said capsaicinoid administration providesan effect selected from the group consisting of: a) producing aselective, highly-localized destruction or incapacitation of C-fibersand/or A-delta fibers in a discrete, localized area responsible for theinitiation of pain for the purpose of reducing or eliminating painarising from a discrete locus, and b) minimizing potential adverseconsequences of C-fiber and/or A-delta activation and or damage outsideof the locus of pain.
 24. The method of claim 1, wherein said pain isassociated with median sternotomy, and the method further comprisesadministering to sternal edges of a human or animal undergoing a mediansternotomy a single injectable or implantable dose-of capsaicinoid in anamount effective to denervate said sternal edges without eliciting aneffect outside the sternal edge location, said dose of capsaicin rangingfrom about 1 μg to about 3000 μg.
 25. The method of claim 1, whereinsaid pain is associated with chronic post-herniorrhapy, and the methodfurther comprises administering to a site where hernia surgery wasperformed in a human or animal a single injectable or implantable doseof a capsaicin in an amount effective to denervate said site withouteliciting an effect outside the site, said dose of capsaicin rangingfrom about 1 μg to about 3000 μg.
 26. The method of claim 1, whereinsaid pain is associated with laparoscopic cholecystectomy, and themethod further comprises administering to a site where said laparoscopiccholecystectomy was performed in a human or animal a single injectableor implantable dose of a capsaicin in an amount effective to denervatesaid site without eliciting an effect outside the site, said dose ofcapsaicin ranging from about 1 μg to about 3000 μg.
 27. The method ofclaim 1, wherein said pain is associated with Morton's Neuroma, and themethod further comprises administering to a digital nerve in a human oranimal in need thereof a single injectable or implantable dose of acapsaicin in an amount effective to denervate said digital nerve withouteliciting an effect outside the digital nerve, said dose of capsaicinranging from about 1 μg to about 3000 μg.
 28. The method of claim 1,wherein said pain is associated with osteoarthritis of the knee, and themethod further comprises administering intra-articularly to a knee of ahuman or animal a single injectable or implantable dose of a capsaicinin an amount effective to denervate said knee without eliciting aneffect outside the knee, said dose of capsaicin ranging from about 1 μgto about 3000 μg.
 29. The method of claim 1, wherein said pain isassociated with tendonitis or bursitis of the shoulder, and the methodfurther comprises administering to a subacromial bura of a human oranimal a single injectable or implantable dose of a capsaicin in anamount effective to denervate said bursa without eliciting an effectoutside the bursa, said dose of capsaicin ranging from about 1 μg toabout 3000 μg.
 30. The method of claim 1, wherein said pain isassociated with epicondylitis, and the method further comprisesadministering into muscle and tissue distal to the lateral/medialepicondyle of a human or animal a single injectable or implantable doseof a capsaicin in an amount effective to denervate said muscle andtissue without eliciting an effect outside the muscle or tissue, saiddose of capsaicin ranging from about 1 μg to about 3000 μg.
 31. Themethod of claim 1, wherein said pain is associated with a bunionectomy,and the method further comprises administering into a wound openingresulting from a bunionectomy surgical procedure in a human or animal asingle injectable or implantable dose of a capsaicin in an amounteffective to denervate said wound opening without eliciting an effectoutside the wound opening, said dose of capsaicin ranging from about 1μg to about 3000 μg.
 32. The method of claim 1, wherein said pain isassociated with a condition selected from the group consisting oftendonitis, bursitis, osteoarthritis, and rheumatoid arthritis.
 33. Themethod of claim 1, wherein said pain is associated with an orthopedicdisorder of the foot selected from the group consisting of heel spurs,corns, bunions, Morton's neuroma, hammertoes, ankle sprain, fractures ofthe ankle or metatarsals or sesamoid bone or toes, plantar fascitis andinjuries to the achilles tendon.
 34. The method of claim 1, wherein saidpain is associated with an orthopedic disorder of the hand selected fromthe group consisting of arthritis, carpal tunnel syndrome, and ganglioncysts.
 35. The method of claim 1, wherein said pain is associated with adisorder selected from the group consisting of lateral epicondylitis,medial epicondylitis, rotator cuff tendonitis, DeQuervian'stenosynovitis, and trigger finger/trigger thumb.
 36. The method of claim1, wherein said pain is associated with a disorder selected from thegroup consisting of Paget's disease, scoliosis, contusions, sprains,strains, lower back pain, and heel spur.
 37. The method of claim 1,wherein said pain is associated with a bone fracture.
 38. The method ofclaim 1, wherein said pain is associated an injury selected from thegroup consisting of a tear of the anterior cruciate ligament, a tear ofthe posterior cruciate ligament, a tear of the medial collateralligament, a tear of the lateral collateral ligament; a meniscalcartilage tear; a cartilage defect of the knee; and combinations of anyof the foregoing.
 39. The method of claim 1, wherein said pain isassociated with an orthopedic disorder of the shoulder selected from thegroup consisting of bursitis, dislocation, separation, impingement andtear of the rotator cuff, tendonitis, adhesive capsulitis, shoulderfracture, and combinations of any of the foregoing.
 40. The method ofclaim 1, wherein said dose of capsaicinoid is therapeutically equivalentto a dose of capsaicin in an amount from about 300 to about 1500 μg. 41.The method of claim 1, wherein said dose of capsaicinoid istherapeutically equivalent to a dose of capsaicin in an amount fromabout 400 to about 1200 μg.
 42. The method of claim 1, wherein thecapsaicinoid is a purified capsaicin.
 43. The method of claim 1, whereinthe capsaicinoid is at least about 97% trans-capsaicin.
 44. The methodof claim 1, wherein said pain at said site is associated with cancerpain.
 45. The method of claim 1, wherein said pain at said site isassociated with a muscle tear.
 46. The method of claim 1, wherein saidcapsaicinoid comprises a mixture of capsaicinoids in a total amountequivalent to a capsaicin dose from about 1 μg to about 5000 μg ofcapsaicin.
 47. The method of claim 1, wherein said pain at said site isassociated with joint pain, and a single unit dose capsaicinoidinjection or implantation attenuates pain at the site for at least aboutone month.
 48. The method of claim 1, wherein said pain at said site isassociated with joint pain, and a single unit dose capsaicinoidinjection or implantation attenuates pain at the site for at least aboutthree months.
 49. The method of claim 1, wherein said pain at said siteis associated with an arthritic condition, and a single unit dosecapsaicinoid injection or implantation attenuates pain at the site forat least about three months.
 50. The method of claim 1, wherein saidpain at said site is post-surgical pain, and a single unit dosecapsaicinoid injection or implantation attenuates pain at the site forat least about one week.
 51. The method of claim 1, further comprisingadministering to said patient an analgesic to treat breakthrough pain.52. A method of treating acute traumatic pain associated with an injury,comprising injecting a capsaicinoid in a physiologically compatiblevehicle through the skin of a patient in proximity to an injury, saiddose of capsaicinoid being sufficient to attenuate the dull, aching painassociated with C-fibers in proximity to the injury and such that thepatient continues to have sensation in proximity to the injury andwithout affecting sharp protective pain associated with A-delta fibersin proximity to the site, the dose of capsaicinoid being therapeuticallyequivalent to a dose of capsaicin in an amount from about 300 to about1500 μg and being effective to attenuate dull, aching pain in proximityto the injury for at least about 48 hours.
 53. An injectable orimplantable pharmaceutical composition for attenuating pain at a site ina human or animal in need thereof, consisting essentially of acapsaicinoid selected from the group consisting of from 1 μg to 5000 μgof capsaicin, a therapeutically equivalent amount of one or more othercapsaicinoids, and combinations thereof; in a pharmaceuticallyacceptable vehicle for injection or implantation.
 54. The pharmaceuticalcomposition of claim 54, wherein said capsaicinoid comprises from about300 μg to 1500 μg capsaicin.
 55. The pharmaceutical composition of claim54, wherein said capsaicinoid comprises from about 400 μg to 1200 μgcapsaicin.
 56. The pharmaceutical composition of claim 54, wherein saidcapsaicinoid comprises from about 300 μg to 1500 μg of trans-capsaicin.57. The pharmaceutical composition of claim 54, wherein the capsaicinoidis at least about 97% trans-capsaicin.
 58. The pharmaceuticalcomposition of claim 53, wherein said pharmaceutically acceptablevehicle is an aqueous vehicle is selected from the group consisting ofSodium Chloride Injection, Ringers Injection, Isotonic DextroseInjection, Sterile Water Injection, Dextrose, Lactated Ringers Injectionand any combinations or mixtures thereof.
 59. The pharmaceuticalcomposition of claim 53, wherein said pharmaceutically acceptablevehicle comprises an agent selected form the group consisting ofantimicrobial agents, isotonic agents, buffers, antioxidants, localanesthetics, suspending and dispersing agents, emulsifying agents,sequestering, chelating agents and any combinations thereof.
 60. Thepharmaceutical composition of claim 53, wherein said pharmaceuticallyacceptable vehicle comprises effective concentrations of polyethyleneglycol, histidine and sucrose, in water for injection.
 61. Thepharmaceutical composition of claim 60, wherein said pharmaceuticallyacceptable vehicle comprises about 20% PEG 300, about 10 mM histidineand about 5% sucrose in water for injection.
 62. An injectable orimplantable pharmaceutical composition for attenuating pain at a site ina human or animal in need thereof, consisting essentially of from 1 μgto 5000 μg of trans-capsaicin and a pharmaceutically acceptable vehiclefor injection or implantation.
 63. The pharmaceutical composition ofclaim 62, wherein said pharmaceutically acceptable vehicle compriseseffective concentrations of polyethylene glycol, histidine and sucrose,in water for injection.
 64. The pharmaceutical composition of claim 62,wherein said pharmaceutically acceptable vehicle comprises about 20% PEG300, about 10 mM histidine and about 5% sucrose in water for injection.65. The composition of claim 62, wherein said trans-capsaicin is presentin an amount from about 300 to about 1500 μg.
 66. The composition ofclaim 62, wherein said trans-capsaicin is present in an amount fromabout 400 to about 1200 μg.